Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)

May combine two claims.

Mice have simpler Bruch's membrane and a different process of lipofuscin extrusion compared with humans.

“However, drusen are rarely seen in mice because of their simpler Bruch’s membrane and different process of lipofuscin extrusion compared with humans.”

May combine two claims.

Focal atrophy of photoreceptors and RPE, lipofuscin accumulation, and increased A2E can develop in aged mouse eyes.

“Although the mouse has no macula, focal atrophy of photorecptors and RPE, lipofuscin accumulation, and increased A2E can develop in aged mouse eyes.”

The quote only partly states this claim.

Murine dry AMD models can be classified into three groups: genetically engineered, immunologically manipulated, and natural mouse strains.

“Based on the multifactorial pathogenesis of AMD, murine dry AMD models can be classified into three groups.”

Classified as probably not a substantial claim. May combine two claims.

Dry AMD pathology consists of degeneration of photoreceptors and the RPE, lipofuscin (A2E) accumulation, and drusen formation.

“The pathology of dry AMD consists of degeneration of photoreceptors and the RPE, lipofuscin (A2E) accumulation, and drusen formation.”

May combine two claims.

All aforementioned murine models develop retinal lesions with various features that simulate dry AMD lesions: focal photoreceptor degeneration, abnormal RPE with increased lipofuscin, basal infolding, decreased melanosomes and degeneration.

“All the aforementioned models develop retinal lesions with various features that simulate dry AMD lesions: focal photoreceptor degeneration, abnormal RPE with increased lipofuscin, basal infolding, decreased melanosomes and degeneration.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There is an age-related increase in thickness in Bruch's membrane and the internal limiting membrane.

“There is an age-related increase in thickness in Bruch’s membrane and the internal limiting membrane (Sarks, 1976; Ding et al., 2009).”

• cites Sarks, 1976 sourceNot checked yet

  Not checked in the free run.

• cites Ding et al., 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Aging induces retinal changes in RPE cell size and shape and results in accumulation of lysosomal residual bodies called lipofuscin granules.

“Aging induces retinal changes in RPE cell size and shape and results in the accumulation of lysosomal residual bodies called lipofuscin granules.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Loss of mitochondria is reported in AMD retina.

“Loss of mitochondria is also reported in AMD retina (Ding et. al, 2009).”

• cites Ding et. al, 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

At the ultrastructural level, drusen are a fine, granular, amorphous material the same electrodensity of the RPE basement membrane with vesicles, tubular structures, curly membranes and abnormal collagen.

“At the ultrastructural level, drusen are a fine, granular, amorphous material the same electrodensity of the RPE basement membrane with vesicles, tubular structures, curly membranes and abnormal collagen (Sarks, 1976).”

• cites Sarks, 1976 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Lipofuscin accumulation in RPE cells, basal deposits, drusen, and thickening of Bruch's membrane are all seen in early AMD and may continue to be present in late stages.

“Lipofuscin accumulation in RPE cells, basal deposits, drusen, and thickening of Bruch’s membrane are all seen in early AMD and may continue to be present in late stages of the disease.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Drusen are subretinal extracellular deposits composed of glycoproteins and lipids in the inner collagenous zone of Bruch's membrane.

“Drusen are subretinal extracellular deposits composed of glycoproteins and lipids in the inner collagenous zone of Bruch’s membrane (Sarks, 1976).”

• cites Sarks, 1976 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Classic pathology of advanced AMD has two forms: geographic atrophic (dry) and neovascular/exudative (wet).

“The classic pathology of advanced AMD is described as having two forms: the ‘geographic atrophic (dry)’ and ‘neovascular/exudative (wet)’ forms.”

May combine two claims.

With age, photoreceptor cells (rods much more than cones, peripheral more than central retina) and ganglion cells decrease in number and density; RPE cells also show parallel changes and progressive cell loss.

“With age, photoreceptor cells (rods much more than cones, peripheral more than central retina) and ganglion cells, decrease in number and density; RPE cells also show parallel changes and progressive cell loss (Gao and Hollyfield, 1992; Panda-Jonas et al., 1995).”

• cites Gao and Hollyfield, 1992Not checked yet

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• cites Panda-Jonas et al., 1995 sourceNot checked yet

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May combine two claims.

BlinD are a more specific marker of AMD progression to late disease, and BlamD are a more reliable indicator of RPE atrophy and photoreceptor degeneration.

“BlinD are a more specific marker of AMD progression to late disease, and BlamD are a more reliable indicator of RPE atrophy and photoreceptor degeneration (van der Schaft et al., 1992; Curcio and Millican, 1999; Sarks, 1976).”

• cites van der Schaft et al., 1992 sourceNot checked yet

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• cites Curcio and Millican, 1999Not checked yet

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• cites Sarks, 1976 sourceNot checked yet

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May combine two claims.

Murine models provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease.

“In summary, murine models provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease.”

Probably not a substantial claim: may not pass S3 (load-bearing).

BlinD are lipid-rich electron dense substances with granules and vesicles external to the RPE basement membrane in the inner collagenous zone.

“BlinD are lipid-rich electron dense substances with granules and vesicles external to the RPE basement membrane in the inner collagenous zone.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

AMD still has an unknown etiology, though oxidative stress to RPE cells along with immune dysregulation are leading theories of AMD pathogenesis.

“AMD still has an unknown etiology, though oxidative stress to the retinal pigment epithelium (RPE) cells along with immune dysregulation are leading theories of AMD pathogenesis (Ding et al., 2009).”

• cites Ding et al., 2009 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Hard, or nodular, drusen are smooth surfaced, dome-shaped structures between the RPE and Bruch's membrane that are clinically common.

“Hard, or nodular, drusen are smooth surfaced, dome-shaped structures between the RPE and Bruch’s membrane that are clinically common.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Large soft drusen are thought to arise from BlinD, which are 24-fold more common in eyes with AMD than age-matched controls.

“Large soft drusen are thought to arise from BlinD, which are 24-fold more common in eyes with AMD than age-matched controls (Curcio and Millican, 1999).”

• cites Curcio and Millican, 1999Not checked yet

  Not checked in the free run.

May combine two claims.

Abnormalities in the distal cone axon occur with aging and increase susceptibility to AMD.

“Recently, it has been noted that abnormalities in the distal cone axon occurs with aging and increases susceptibility to AMD (Shelley et al., 2009).”

• cites Shelley et al., 2009 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Classic pathology of early AMD is multiple small or intermediate drusen (drusen size ≥63 microns but <125 microns) in the macular area.

“The classic pathology of early AMD is multiple small or intermediate drusen (drusen size of ≥ 63 microns but < 125 microns) in the macular area (Coleman et al., 2008).”

• cites Coleman et al., 2008 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Patients with drusen and CNV have higher circulating levels of anti-retinal antibodies compared to controls.

“Additionally, patients with drusen and CNV have higher circulating levels of anti-retinal antibodies compared to controls (Patel et al., 2005)”

• cites Patel et al., 2005 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Drusen contain acute phase proteins, complement pathway components and inhibitors, apolipoproteins B and E, mucopolysaccarides, lipids, mannose, and sialic acid.

“Studies analyzing the composition of drusen have shown that drusen contain acute phase proteins (C-reactive protein, vitronectin, α-antichymotrypsin, amyloid P component, and fibrinogen), complement pathway components (C3, C5 and C5b-9 complex) and inhibitors (clusterin), apolipoproteins B and E, mucopolysaccarides, lipids, mannose, and sialic acid (Farkas et al., 1971; Mullins et al., 2000).”

• cites Farkas et al., 1971 sourceNot checked yet

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• cites Mullins et al., 2000 sourceNot checked yet

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May combine two claims.

Cone degeneration and red-green cone hypertrophy are also found in advanced dry AMD.

“Cone degeneration and red-green cone hypertrophy are also found.”

May combine two claims.

Low ERp29 levels impact chaperone function and lead to accumulation of misfolded proteins which may aggregate and interfere with intracellular movement, allowing for aggregation of incompletely folded compounds such as lipofuscin and drusen to cause RPE damage.

“Low ERp29 levels impacts chaperone function and lead to the accumulation of misfolded proteins which may aggregate and interfere with intracellular movement, allowing for the aggregation of incompletely folded compounds such as lipofuscin and drusen to cause RPE damage (Li et al., 2004; Ethen et al., 2006).”

• cites Li et al., 2004Not checked yet

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• cites Ethen et al., 2006 sourceNot checked yet

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May combine two claims.

Lower levels of ERp29 are found in neurodegenerative diseases, in the AMD maculae, and the aging retina.

“Lower levels of the endoplasmic reticulum chaperone protein ERp29 are found in neurodegenerative diseases, in the AMD maculae, and the aging retina.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Dry AMD consists of perturbations in RPE, Bruch's membrane, photoreceptors, and choriocapillaris, leading to photoreceptor degeneration and atrophy.

“The ‘dry’ form of AMD, non-neovascular AMD, including intermediate AMD with many intermediate or large drusen (drusen size of ≥ 125 microns) and RPE alterations and advanced AMD with geographic atrophy, consists of many perturbations in the RPE, Bruch’s membrane, photoreceptors, and choriocapillaris, leading to photoreceptor degeneration and atrophy.”

Probably not a substantial claim: may not pass S3 (load-bearing).

There are two types of basal deposits: basal laminar deposits (BlamD) and basal linear deposits (BlinD).

“There are two types of basal deposits: basal laminar deposits (BlamD) and basal linear deposits (BlinD).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The retina adjacent to areas of geographic atrophy (junctional zones) is hyperpigmented and has hypertrophied RPE cells with occasional multinucleated giant cells.

“The retina adjacent to the areas of geographic atrophy (junctional zones) is hyperpigmented and has hypertrophied RPE cells with occasional multinucleated giant cells (Dastgheib and Green, 1994).”

• cites Dastgheib and Green, 1994Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

This profile does not significantly change with progression from early AMD to advanced stage AMD.

“and this profile does not significantly change with progression from early AMD to advanced stage AMD (Cherepanoff et al., 2006).”

• cites Cherepanoff et al., 2006 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

CNV is the hallmark of wet AMD.

“New blood vessel formation from the choroid, known as choroidal neovascularization (CNV), is the hallmark of ‘wet’ AMD.”

May combine two claims.

RPE progressively accumulates lipofuscin, leaving partially digested photoreceptors in the cytoplasm.

“The RPE progressively accumulates lipofuscin, leaving partially digested photoreceptors in the cytoplasm.”

May combine two claims.

In advanced dry AMD called geographic atrophy, the RPE has well-demarcated atrophy and the neurosensory retina is severely affected.

“In the advanced stage of dry AMD called geographic atrophy, the RPE has well-demarcated atrophy and the neurosensory retina is severely affected (Coleman et al., 2008).”

• cites Coleman et al., 2008 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Photoreceptor cell loss is most prominent in the parafovea and can progress to total photoreceptor loss and disciform degeneration.

“Photoreceptor cell loss is most prominent in the parafovea and can progress to total photoreceptor loss and disciform degeneration (Curcio et al., 1996; Sarks, 1976; Shelley et al., 2009).”

• cites Curcio et al., 1996Not checked yet

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• cites Sarks, 1976 sourceNot checked yet

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• cites Shelley et al., 2009 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Hemorrhages, exudates, and neovascular fibrous tissue may replace normal retinal architecture and result in photoreceptor atrophy.

“Hemorrhages, exudates, and neovascular fibrous tissue may replace normal retinal architecture and result in photoreceptor atrophy (Green, 1999; Kim et al., 2002).”

• cites Green, 1999Not checked yet

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• cites Kim et al., 2002 sourceNot checked yet

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May combine two claims.

At 20 months of age, Ccl2−/− mice began to overexpress VEGF in the RPE, had dilated choriocapillaries, and began to have fragmentation in the outer layer of Bruch's membrane.

“At 20 months of age, Ccl2−/− mice began to overexpress VEGF in the RPE, had dilated choriocapillaries, and began to have fragmentation in the outer layer of Bruch’s membrane (Ambati et al., 2003).”

• cites Ambati et al., 2003 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Ccr2−/− mice displayed signs of late AMD with geographic atrophy, outer retinal degeneration, and CNV.

“Ccr2−/− mice also displayed signs of late AMD with geographic atrophy, outer retinal degeneration, and CNV.”

• cites Ambati et al., 2003 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

As Ccl2−/− mice aged, they exhibited many findings of advanced AMD, including geographic atrophy, progressive outer retinal degeneration, and CNV.

“As Ccl2−/− mice aged, they exhibited many of the findings of advanced AMD, including geographic atrophy, progressive outer retinal degeneration, and CNV (Ambati et al., 2003).”

• cites Ambati et al., 2003 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Subretinal fibrous tissue, or minimal subretinal fibrosis, and widespread RPE atrophy are also often noted in neovascular AMD.

“Subretinal fibrous tissue, or minimal subretinal fibrosis, and widespread RPE atrophy are also often noted (Coleman et al., 2008).”

• cites Coleman et al., 2008 sourceNot checked yet

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May combine two claims.

At 14 months of age, Ccl2−/− mice had healthy photoreceptors, but attenuated and pyknotic photoreceptors developed by 16 months of age, while wild type mice still had normal photoreceptors.

“At 14 months of age, photoreceptors were healthy, but attenuated and pyknotic photoreceptors developed by 16 months of age, while wild type mice still had normal photoreceptors (Ambati et al., 2003).”

• cites Ambati et al., 2003 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

After 9 months of age, subretinal deposits with features of drusen were observed in all Ccl2−/− mice, and the number of deposits increased with age.

“After 9 months of age, subretinal deposits with features of drusen were observed in all Ccl2−/− mice, and the number of deposits increased with age.”

• cites Ambati et al., 2003 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Sclerosis of the choriocapillaris is found without breaks in Bruch's membrane.

“Additionally, sclerosis of the choriocapillaris is found without breaks in Bruch’s membrane (Sarks, 1976).”

• cites Sarks, 1976 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The cfh−/− mice do not have many features of AMD; rather, thinning of Bruch's membrane and decreased drusen were found.

“Though there is a touted association between CFH and AMD, the cfh−/− mice do not have many features of AMD; rather, thinning of Bruch’s membrane and decreased drusen were found.”

May combine two claims.

cfh−/− mice have C3 accumulation in the retina, secondary C3 deficiency, and uncontrolled C3 activation.

“The cfh−/− mice had C3 accumulation in the retina, secondary C3 deficiency, and uncontrolled C3 activation, which may increase phagocytic uptake and cause neural damage to the retina (Mullins et al., 2000; Coffey et al., 2007).”

• cites Mullins et al., 2000 sourceNot checked yet

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• cites Coffey et al., 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

cfh−/− mice have significant thinning of Bruch's membrane by 29% and consistently disorganized, misaligned photoreceptor outer segments.

“Ultrastructurally, cfh−/− mice have significant thinning of Bruch’s membrane (by 29%) and consistently disorganized, misaligned photoreceptor outer segments.”

• cites Coffey et al., 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CFH negatively regulates the complement system by inhibiting the alternative pathway either by promoting Factor I-mediated inactivation of C3b or by displacing Factor Bb from the C3bBb complex.

“CFH negatively regulates the complement system by inhibiting the alternative pathway either by promoting Factor I-mediated inactivation of C3b or by displacing Factor Bb from the C3bBb complex (Alsenz et al., 1985).”

• cites Alsenz et al., 1985 sourceNot checked yet

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May combine two claims.

Homozygous deficiency of CFH in humans and mice results in complement factor alternative pathway dysregulation, membranoproliferative glomerulonephritis type II (MPGN2), and an AMD-like phenotype.

“Homozygous deficiency of CFH in humans and mice results in complement factor alternative pathway dysregulation, the inflammatory renal disease membranoproliferative glomerulonephritis type II (MPGN2), and an AMD-like phenotype (Raines et al., 1989; Leys et al., 1991).”

• cites Raines et al., 1989 sourceNot checked yet

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• cites Leys et al., 1991 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

When Bruch's membrane becomes calcified and focal breaks occur, new blood vessels from the choroid form in the space under the RPE, and this CNV is the hallmark of exudative/neovascular, or 'wet' AMD.

“When Bruch’s membrane becomes calcified and focal breaks occur, new blood vessels from the choroid form in the space under the RPE, and this CNV is the hallmark of exudative/neovascular, or ‘wet’ AMD (Spraul and Grossniklaus, 1997).”

• cites Spraul and Grossniklaus, 1997Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

IgG antibodies against retinal antigens are present in a complex and specific pattern in wet AMD eyes, which differs from dry AMD eyes and healthy controls.

“IgG antibodies against retinal antigens are present in a complex and specific pattern in wet AMD eyes, which differs from dry AMD eyes and healthy controls (Joachim et al., 2007).”

• cites Joachim et al., 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

At 9 months of age, RPE cells in Ccl2−/− mice became swollen, vacuolated, and accumulated high electron density intracellular dense bodies.

“At 9 months of age, RPE cells became swollen, and vacuolated and high electron density intracellular dense bodies, likely melanosomes or melanolipofuscin fusion granules, accumulated.”

• cites Ambati et al., 2003 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

At 18 months of age, Cx3cr1−/− mice had significant (40%) thinning of the outer retina, mainly the outer nuclear layer, which progressed to marked degeneration of the photoreceptor layer by 4 months of age when compared to wild-type mice.

“At this age, the Cx3cr1−/− mice had significant (40%) thinning of the outer retina, mainly the outer nuclear layer, which progressed to marked degeneration of the photoreceptor layer by 4 months of age when compared to wild-type mice.”

• cites Combadiere et al., 2007 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Neovascular AMD often causes sudden loss of vision and presents with serous or hemorrhagic detachment of either the RPE or sensory retina.

“Neovascular AMD often causes sudden loss of vision and presents with serous or hemorrhagic detachment of either the retinal pigment epithelium or sensory retina.”

May combine two claims.

At 10 months of age, 86% of Sod1−/− mice had drusen, compared to very few drusen in age-matched wild-type mice.

“At 10 months of age, 86% of mice had drusen, compared to very few drusen in age-matched wild-type mice (Imamura et al., 2006).”

• cites Imamura et al., 2006 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Aged apoE4 TR mice on a high-fat diet had the most severe degenerative phenotype with RPE hyperpigmentation, hypopigmentation, atrophy, disorganization of basal infoldings with electron-dense deposits, many electron-dense sub-RPE basal deposits, lipid-rich "drusenoid" deposits, disorganization with varying thickness of Bruch's membrane, and CNV of varying severity.

“Aged apoE4 TR mice on a high-fat diet had the most severe degenerative phenotype with RPE hyperpigmentation, hypopigmentation, atrophy, disorganization of basal infoldings with electron-dense deposits, many electron-dense sub-RPE basal deposits, lipid-rich “drusenoid” deposits, disorganization with varying thickness of Bruch’s membrane, and CNV of varying severity (Malek et al., 2005).”

• cites Malek et al., 2005 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In 27 month-old Neprilysin−/− mice, the RPE developed vacuolization, loss of tight and adherence junctions, prominent basal infoldings, and subretinal accumulation of amorphous deposits and photoreceptor outer segments, implying RPE dysfunction.

“In 27 month-old Neprilysin−/− mice, the RPE developed vacuolization, loss of the tight and adherence junctions, prominent basal infoldings, and subretinal accumulation of amorphous deposits and photoreceptor outer segments, implying RPE dysfunction.”

• cites Yoshida et al., 2005 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These lesions progressed to large, confluent areas of yellow deposits in the deep retina and subretinal space by 4-6 months of age and flattened atrophic areas by 6 months of age.

“These lesions progressed to large, confluent areas of yellow deposits in the deep retina and subretinal space by 4–6 months of age and flattened atrophic areas by 6 months of age (Chan et al., 2008).”

• cites Chan et al., 2008 sourceNot checked yet

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May combine two claims.

Evidence of focal CNV was present in 75% of 12-13 month-old Cp−/−Heph−/Y mice and 50% of 7-9 month-old mice.

“Evidence of focal CNV was also present in 75% of 12–13 month-old mice and 50% of 7–9 month-old mice (Hahn et al., 2004; Hadziahmetovic et al., 2008).”

• cites Hahn et al., 2004 sourceNot checked yet

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• cites Hadziahmetovic et al., 2008 sourceNot checked yet

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May combine two claims.

The Ccl2−/−/Cx3cr1−/− mouse model demonstrates many AMD features: small drusenoid deposits, RPE and Bruch's membrane degenerations, photoreceptor atrophy, CNV, and simulation of the immunologic and pathologic environments found in AMD patients.

“The Ccl2−/−/Cx3cr1−/− mouse model demonstrates many AMD features: small drusenoid deposits, RPE and Bruch’s membrane degenerations, photoreceptor atrophy, CNV, and simulation of the immunologic and pathologic environments found in AMD patients (Herzlich et al., 2008; Ross et al., 2008; Ding et al., 2009).”

• cites Herzlich et al., 2008 sourceNot checked yet

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• cites Ross et al., 2008 sourceNot checked yet

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• cites Ding et al., 2009 sourceNot checked yet

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May combine two claims.

Neprilysin−/− mice have enhanced VEGF expression and diminished PEDF expression with no evidence of CNV or leakage on fluorescein angiography.

“The Neprilysin−/− mice have enhanced VEGF expression and diminished PEDF expression with no evidence of CNV or leakage on fluorescein angiography (Yoshida et al., 2005).”

• cites Yoshida et al., 2005 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

By 18 months of age, minimal Bruch's membrane thickening, drusen-like sub-RPE deposits, and extensive BlamD and BlinD were observed in mcd/mcd mice.

“By 18 months of age, minimal Bruch’s membrane thickening, drusen-like sub-RPE deposits, and extensive BlamD and BlinD were observed.”

• cites Rakoczy et al., 2002 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The retina has the highest oxygen consumption of any tissue in the body.

“The retina has the highest oxygen consumption of any tissue in the body (Sickel, 1972).”

• cites Sickel, 1972 sourceNot checked yet

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May combine two claims.

After 9 months on a high fat/cholesterol diet, 100% of APO*E3 Leiden mice eyes have BlamD, while 33% of APO*E3 Leiden mice on a normal diet have BlamD.

“After 9 months on a high fat/cholesterol diet, 100% of APO*E3 Leiden mice eyes have BlamD, while 33% of APO*E3 Leiden mice on a normal diet have BlamD (Kliffen et al., 2000).”

• cites Kliffen et al., 2000 sourceNot checked yet

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May combine two claims.

The apoB100 transgenic mice have higher serum total and LDL cholesterol and a statistically significant cholesterol-dependent increase in Bruch's membrane thickness.

“The apoB100 transgenic mice have higher serum total and LDL cholesterol and a statistically significant cholesterol-dependent increase in Bruch’s membrane thickness (Sallo et al., 2009).”

• cites Sallo et al., 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

At 6-9 months old, Cp−/−Heph−/Y mice had severe retinal degeneration with RPE hypopigmentation, hypertrophy, hyperplasia, and necrosis.

“At 6–9 months old, Cp−/−Heph−/Y mice had severe retinal degeneration with RPE hypopigmentation, hypertrophy, hyperplasia, and necrosis.”

• cites Hahn et al., 2004 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

By 5-6 months of age, the Cp−/−Heph−/Y mice had increased iron levels, and the highest iron levels were in the RPE and photoreceptor OS.

“By 5–6 months of age, the Cp−/−Heph−/Y mice had increased iron levels, and the highest iron levels were in the RPE and photoreceptor OS.”

• cites Hahn et al., 2004 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Tight junctions and basal polarity of the RPE nucleus was lost in the mcd2/mcd2 mice.

“Tight junctions and basal polarity of the RPE nucleus was lost in the mcd2/mcd2 mice (Zhang et al., 2005).”

• cites Zhang et al., 2005 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Smoking is a well-documented AMD risk factor, and a recent meta-analysis showed that current smoking nearly triples AMD incidence.

“Smoking, a common mechanism for generating oxidative stress, is a well-documented AMD risk factor, and a recent meta-analysis showed that current smoking nearly triples AMD incidence (Neuner et al., 2009).”

• cites Neuner et al., 2009 sourceNot checked yet

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May combine two claims.

Sod2 knockdown mice had RPE and Bruch's membrane changes and accumulated A2E and lipofuscin granules in the RPE.

“The Sod2 knockdown mice had RPE and Bruch’s membrane changes and accumulated A2E and lipofuscin granules in the RPE (Justilien et al., 2007).”

• cites Justilien et al., 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

On fundoscopic exam at 9 months of age, RPE hypopigmentation, hyperpigmentation, and drusenoid lesions were present in most mcd/mcd mice, while no lesions were present in wild-type mice.

“On fundoscopic exam at 9 months of age, RPE hypopigmentation, hyperpigmentation, and drusenoid lesions were present in most mcd/mcd mice, while no lesions were present in wild-type mice.”

• cites Rakoczy et al., 2002 sourceNot checked yet

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May combine two claims.

At 6 months, arrd2/arrd2 mice had subnormal rod and cone ERG responses and an undetectable ERG response at 22 months.

“At 6 months, the arrd2/arrd2 mice had subnormal rod and cone ERG responses and an undetectable ERG response at 22 months.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The location of MDM1 on chromosome 12q has previously been reported to be an AMD susceptibility locus.

“though this location has previously been reported to be an AMD susceptibility locus”

• cites Chang et al., 2008 sourceNot checked yet

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• cites Iyengar et al., 2004 sourceNot checked yet

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• cites Fisher et al., 2005 sourceNot checked yet

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Classified as probably not a substantial claim.

As AMD is an age-related phenomenon, the retinas of SAM mice may provide insight into the causes of naturally occurring alterations in the aging human retina.

“As AMD is an age-related phenomenon, the retinas of these mice may provide insight into the causes of naturally occurring alterations in the aging human retina.”

• AssumptionRests on an assumption: AMD is an age-related phenomenon.

May combine two claims.

The photoreceptor layer in Mfrprd6 mice degenerates to 33% of its original thickness by 4.5 months of age, 15% of normal by 7 months of age, and becomes 1 cell layer thick by 24 months of age.

“The photoreceptor layer degenerates to 33% of its original thickness by 4.5 months of age, 15% of normal by 7 months of age, and becomes 1 cell layer thick by 24 months of age”

• cites Kameya et al., 2002 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

arrd2/arrd2 mice also have retinal vascular attenuation, RPE hypo-pigmentation and atrophy at 14 months.

“The arrd2/arrd2 mice also have retinal vascular attenuation, RPE hypo-pigmentation and atrophy at 14 months.”

May combine two claims.

At 4 months of age, arrd2/arrd2 mice had early photoreceptor outer segment degeneration, increased phagosomes and debris in the RPE, normal ONL, swollen synaptic complexes, and large mitochondria.

“At 4 months of age, the arrd2/arrd2 mice had early photoreceptor outer segment degeneration, increased phagosomes and debris in the RPE, normal ONL, swollen synaptic complexes, and large mitochondria.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The inheritance pattern of Nr2e3rd7 is autosomal recessive, and Nr2e3 is mapped to mouse chromosome 9 and human chromosome 15q23.

“The inheritance pattern is autosomal recessive, and Nr2e3 is mapped to mouse chromosome 9 and human chromosome 15q23.”

May combine two claims.

Mfrp is expressed at high levels exclusively in the RPE and ciliary epithelium and not the neural retina.

“Mfrp, expressed at high levels exclusively in the RPE and ciliary epithelium and not the neural retina”

• cites Kameya et al., 2002 sourceNot checked yet

  Not checked in the free run.

• cites Xu and Nusse, 1998Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Mfrp has strong homology to the cysteine-rich domain of frizzled, a protein that is an important member of the Wnt family of proteins.

“has strong homology to the cysteine-rich domain of frizzled, a protein that is an important member of the Wnt family of proteins”

• cites Kameya et al., 2002 sourceNot checked yet

  Not checked in the free run.

• cites Xu and Nusse, 1998Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The Senescence-Accelerated Mouse (SAM) family is a collection of mouse strains with naturally occurring premature aging and associated pathologies.

“An accelerated aging model, the Senescence-Accelerated Mouse (SAM) family, is a collection of mouse strains with naturally occurring premature aging and associated pathologies”

• cites Takeda, 1997 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

At 9 months of age, arrd2/arrd2 mice had fragmented photoreceptor outer segments, abundant phagosomes with loss of the apical processes in the RPE, thinning of the outer plexiform layer (INL and ONL), swollen and necrotic synaptic terminals, and mitochondrial edema.

“At 9 months of age, the arrd2/arrd2 mice had fragmented photoreceptor outer segments, abundant phagosomes with loss of the apical processes in the RPE, thinning of the outer plexiform layer (INL and ONL), swollen and necrotic synaptic terminals, and mitochondrial edema.”

May combine two claims.

Homozygous Mfrprd6 mice have diminished ERG responses beginning at 1 month of age, supportive of a slow progressive retinal rod and cone dysfunction that culminates in extinguished ERG activity by 70 weeks of age.

“Homozygous Mfrprd6 mice have diminished ERG responses beginning at 1 month of age, supportive of a slow progressive retinal rod and cone dysfunction that culminates in extinguished ERG activity by 70 weeks of age.”

May combine two claims.

RPE cells in CEP-immunized mice had vesiculation, pyknosis, lysis, and areas of RPE loss with overlying swollen photoreceptors.

“The RPE cells in CEP-immunized mice had vesiculation, pyknosis, lysis, and areas of RPE loss with overlying swollen photoreceptors.”

• cites Hollyfield et al., 2008 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The rd6 retinal degeneration is inherited in an autosomal recessive manner and maps to mouse chromosome 9 with a human homolog on chromosome 11q23.

“One of the naturally occurring retinal degeneration and retinitis pigmentosa models, rd6, is inherited in an autosomal recessive manner and maps to mouse chromosome 9 with a human homolog on chromosome 11q23”

• cites Hawes et al., 2000Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The first identified retinal degeneration model was RdsRd2, an autosomal dominant slow retinal degeneration identified in inbred mice that accumulated an insertion of foreign DNA into an exon of Rds.

“The first identified retinal degeneration model was RdsRd2, an autosomal dominant slow retinal degeneration identified in inbred mice that accumulated an insertion of foreign DNA into an exon of Rds”

• cites Sanyal and Hawkins, 1986Not checked yet

  Not checked in the free run.

• cites van Nie et al., 1978 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Homozygous Mfrprd6 mice have pan-retinal drusen-like deposits on fundoscopy at 8 weeks of age that progress to advanced retinal degeneration by 8 months of age, and these lesions are associated with macrophage invasion of the sub-retinal space and retinal dysplasia.

“The homozygous Mfrprd6 mice have pan-retinal drusen-like deposits on fundoscopy at 8 weeks of age that progress to advanced retinal degeneration by 8 months of age, and these lesions are associated with macrophage invasion of the sub-retinal space and retinal dysplasia”

• cites Hawes et al., 2000Not checked yet

  Not checked in the free run.

May combine two claims.

CEP-immunized mice had C3d in Bruch's membrane, signifying that an intact immune system responds to CEP immunization with sub-RPE complement deposition, a feature of AMD.

“Immunized mice had C3d, a C3b degradation product in Bruch’s membrane, signifying that an intact immune system responds to CEP immunization with sub-RPE complement deposition, a well-known feature of AMD”

• cites Hollyfield et al., 2008 sourceNot checked yet

  Not checked in the free run.

• cites Patel and Chan, 2008Not checked yet

  Not checked in the free run.

May combine two claims.

The general structure of the immune system in mice and humans is very similar, though discrepancies in both the innate and adaptive immune system exist.

“The general structure of the immune system in mice and humans is also very similar, though discrepancies in both the innate and adaptive immune system exist”

• cites Haley, 2003 sourceNot checked yet

  Not checked in the free run.

• cites Mestas and Hughes, 2004 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Histologic analysis of the photoreceptor ONL in Nr2e3rd7 mice demonstrates retinal dysplasia with whorls and rosettes, which decrease by 5 months of age and disappear when the photoreceptor layer flattens to 5-cell layers thick.

“Histologic analysis of the photoreceptor ONL demonstrates retinal dysplasia with whorls and rosettes, which decrease by 5 months of age and disappear when the photoreceptor layer flattens to 5-cell layers thick.”

May combine two claims.

Gnat2cpfl3 mice have normal rod responses on ERG with an abnormal, significantly reduced, photopic response that was extinguished by 9 months of age.

“Gnat2cpfl3 mice have normal rod responses on ERG with an abnormal, significantly reduced, photopic response that was extinguished by 9 months of age.”

May combine two claims.

SAMP8 mice have a shortened life-span, learning and memory deficits, features of AMD, and no signs of brain atrophy.

“The SAMP8 mice have a shortened life-span, learning and memory deficits, features of AMD, and no signs of brain atrophy”

• cites Kawamata et al., 1997 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The described murine models of dry AMD have drusenoid lesions and RPE atrophy on fundoscopy, ERG abnormalities, A2E accumulation, sub-RPE basal deposits, and Bruch's membrane thickening.

“The described murine models of dry AMD have drusenoid lesions and RPE atrophy on fundoscopy, ERG abnormalities, A2E accumulation, sub-RPE basal deposits, and Bruch’s membrane thickening (Table 2).”

May combine two claims.

By 25 months of age, SAMR1 mice had near complete loss of the photoreceptor layer peripherally and significant loss of the photoreceptor and ganglion cells centrally.

“By 25 months of age, SAMR1 mice had near complete loss of the photoreceptor layer peripherally and significant loss of the photoreceptor and ganglion cells centrally”

• cites Shoji et al., 1998 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Nr2e3 is part of the cellular and nuclear receptor family for steroid hormones and is involved in cone cell proliferation, maintenance of photoreceptor topography and intercellular interactions, and expression of rod photoreceptor cell-specific genes.

“Nr2e3 is part of the cellular and nuclear receptor family for steroid hormones and is involved in cone cell proliferation, maintenance of photoreceptor topography and intercellular interactions, and expression of rod photoreceptor cell-specific genes”

• cites Fuller, 1991 sourceNot checked yet

  Not checked in the free run.

• cites Haider et al., 2001 sourceNot checked yet

  Not checked in the free run.

• cites Cheng et al., 2004 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The retinal ultrastructure of Nr2e3rd7 mice demonstrates disorganized photoreceptor outer segments and apical microvilli retardation in the RPE cells.

“The retinal ultrastructure demonstrates disorganized photoreceptor outer segments and apical microvilli retardation in the RPE cells”

• cites Won et al., 2008 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Nr2e3rd7 mice have additional retinal vascular attenuation and mottled retinal pigmentation at 16 months of age.

“There is additional retinal vascular attenuation and mottled retinal pigmentation at 16 months of age”

• cites Chang et al., 1998Not checked yet

  Not checked in the free run.

• cites Haider et al., 2001 sourceNot checked yet

  Not checked in the free run.

• cites Akhmedov et al., 2000 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In AMD, cones lose their synaptic connections before dying, and signs of photoreceptor degeneration are found in cones before rods.

“in AMD, cones lose their synaptic connections before dying, and signs of photoreceptor degeneration are found in cones before rods”

• cites Shelley et al., 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A mutation in exon 6 of Gnat2 results in a missense mutation of the α-subunit of transducin, preventing photoreceptor hyperpolarization in the light transduction cascade, resulting in loss of function in the structurally normal cones in cpfl3/cpfl3 mice.

“A mutation in exon 6 of Gnat2 results in a missense mutation of the α-subunit of transducin, preventing photoreceptor hyperpolarization in the light transduction cascade, resulting loss of function in the structurally normal cones in cpfl3/cpfl3 mice.”

May combine two claims.

Pathologic hallmarks of dry AMD include drusen accumulation (BlamD and BlinD), Bruch's membrane thickening, RPE lipofuscin accumulation followed by degeneration, and photoreceptor degeneration and atrophy.

“Pathologic hallmarks of dry AMD include drusen accumulation (BlamD and BlinD), Bruch’s membrane thickening, RPE lipofuscin accumulation followed by degeneration, and photoreceptor degeneration and atrophy.”

May combine two claims.

The naturally occurring mouse models include retinal degeneration models with mutations in Mdm1, Mfrp, Nr2e3, and Gnat2 with significant photoreceptor pathology and the SAM models with systemic and retinal age-related pathology, including Bruch's membrane thickening, basal deposits, and CNV.

“The naturally occurring mouse models include retinal degeneration models with mutations in Mdm1, Mfrp, Nr2e3, and Gnat2 with significant photoreceptor pathology and the senescence-accelerated mouse (SAM) models with systemic and retinal age-related pathology, including Bruch’s membrane thickening, basal deposits, and CNV.”

May combine two claims.

SAMP mice are short-lived and have double the aging features when compared to the SAMR mice at 8 months of age.

“The SAMP mice are short-lived and have double the aging features when compared to the SAMR mice at 8 months of age”

• cites Takeda, 1997 sourceNot checked yet

  Not checked in the free run.

• cites Takeda et al., 1994 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Fundoscopy of cpfl3/cpfl3 mice shows no retinal lesions and only dilated retinal vessels at 8 months of age.

“Fundoscopy of cpfl3/cpfl3 mice shows no retinal lesions and only dilated retinal vessels at 8 months of age.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

Working with primates, the only mammals with a macula, may have scientific advantages.

“Working with primates, the only mammals with a macula, may have scientific advantages.”

The quote only partly states this claim.

BlamD, amorphous deposits in the sub-RPE space on the RPE side of Bruch's membrane, were also found in SAM mice.

“BlamD, amorphous deposits in the sub-RPE space on the RPE side of Bruch’s membrane, were also found”

• cites Majji et al., 2000Not checked yet

  Not checked in the free run.

May combine two claims.

A mouse with a naturally occurring mutation in cone photoreceptor function loss-3 (cpfl3) is being used as a model for rod monochromism, or achromatopsia, an autosomal recessive disease in which there is a loss of functional retinal cone photoreceptors, resulting in a disease that presents in infancy with horizontal nystagmus, photophobia, color blindness, and poor visual acuity.

“A mouse with a naturally occurring mutation in cone photoreceptor function loss-3 (cpfl3) is being used a model for rod monochromism, or achromatopsia, an autosomal recessive disease in which there is a loss of functional retinal cone photoreceptors, resulting in a disease that presents in infancy with horizontal nystagmus, photophobia, color blindness, and poor visual acuity”

• cites Aligianis et al., 2002 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Sequencing of mouse and human genomes reveals great conservation of function and only about 300 unique genes.

“sequencing of mouse and human genomes reveals great conservation of function and only about 300 unique genes”

• cites Waterston et al., 2002 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

While the cpfl3 model does not have the Bruch's membrane, RPE, and choriocapillaris changes seen in AMD patients, it demonstrates the cone pathology and dysfunction that can be present in the AMD macula.

“While this model does not have the Bruch’s membrane, RPE, and choriocapillaris changes seen in AMD patients, it demonstrates the cone pathology and dysfunction that can be present in the AMD macula.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Aging, or senescence, has been shown to be associated with photoreceptor loss in humans and in murine models.

“Aging, or senescence, has been shown to be associated with photoreceptor loss in humans and in murine models”

• cites Gao and Hollyfield, 1992Not checked yet

  Not checked in the free run.

• cites Katz and Robison, 1986Not checked yet

  Not checked in the free run.

May combine two claims.

As SAMP1 and SAMP8 mice age, deposition of fine fibrils in Bruch's membrane increases, resulting in a four-fold increase in thickness of Bruch's membrane by 8 months of age.

“As the SAMP1 and SAMP8 mice age, deposition of fine fibrils in Bruch’s membrane increases, resulting in a four-fold increase in thickness of Bruch’s membrane by 8 months of age”

• cites Takada et al., 1993Not checked yet

  Not checked in the free run.

• cites Majji et al., 2000Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

These models contrast with the murine models of wet AMD that are mostly induced mechanically.

“These models contrast with the murine models of wet AMD that are mostly induced mechanically.”

May combine two claims.

ERGs of homozygous Nr2e3rd7 mice show progressive reduction of both rod and cone signals starting at 5 months of age, and wave amplitudes were 50% of normal by 16 months of age.

“ERGs of homozygous Nr2e3rd7 mice show progressive reduction of both rod and cone signals starting at 5 months of age, and wave amplitudes were 50% of normal by 16 months of age”

• cites Akhmedov et al., 2000 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The RPE cells in SAM mice have swelling of basal infoldings and accumulation of lipofuscin granules that increase with age.

“The RPE cells in SAM mice have swelling of basal infoldings and accumulation of lipofuscin granules that increase with age”

• cites Ogata et al., 1992Not checked yet

  Not checked in the free run.

May combine two claims.

Aged primates have macular degeneration that presents in the late 20s with soft drusen and an immunophenotype of drusen very similar to that of humans.

“Aged primates have macular degeneration that presents in the late 20s with soft drusen and an immunophenotype of drusen very similar to that of humans”

• cites Umeda et al., 2005Not checked yet

  Not checked in the free run.

May combine two claims.

In SAMP8 mice, early disruption of the RPE basal microvilli begins at 8 months of age and progresses to severe RPE degeneration by 12 months of age.

“In SAMP8 mice, early disruption of the RPE basal microvilli begins at 8 months of age and progresses to severe RPE degeneration by 12 months of age”

• cites Majji et al., 2000Not checked yet

  Not checked in the free run.

May combine two claims.

The immunologically manipulated mouse model was immunized against CEP, an endogenous biomarker of oxidative stress, and its phenotype consisted of immune dysregulation and complement deposition as seen in AMD.

“The immunologically manipulated mouse model was immunized against CEP, an endogenous biomarker of oxidative stress, and its phenotype consisted of immune dysregulation and complement deposition as seen in AMD.”

May combine two claims.

Therapies that have been shown to work in mice have failed in human trials, and therapies that do not work in mice have shown success in humans.

“Therapies that have been shown to work in mice have failed in human trials, and therapies that do not work in mice have shown success in humans”

• cites Shepherd and Sridhar, 2003Not checked yet

  Not checked in the free run.

• cites Panitch et al., 1987 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

hESC-derived RPE cells were subretinally transplanted into the ELOVL4-mutant mouse and rats with retinal degeneration (RSC rats), followed for >220 days, and shown to recover visual function and photoreceptor integrity without complications.

“human embryonic stem cell (hESC)-derived RPE cells were subretinally transplanted into the ELOVL4-mutant mouse and rats with retinal degeneration (RSC rats). These mice were followed for a prolonged period (>220 days) and shown to recover visual function and photoreceptor integrity without complications”

• cites Lu et al., 2009Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable).

Mouse models will likely play a critical role in the future of AMD research, as they may answer many specific questions at the molecular level, potentially providing further insight into the pathogenesis of this disease.

“Mouse models will likely play a critical role in the future of AMD research, as they may answer many specific questions at the molecular level, potentially providing further insight into the pathogenesis of this disease.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The usage of cyclosporine, rapamycin, or daclizumab for uveitis is based on its effectiveness in experimental autoimmune uveitis.

“the usage of cyclosporine, rapamycin, or daclizumab for uveitis is based on its effectiveness in experimental autoimmune uveitis”

• cites Nussenblatt, 2002 sourceNot checked yet

  Not checked in the free run.

• cites Martin et al., 1995 sourceNot checked yet

  Not checked in the free run.

• cites Nussenblatt et al., 1983 sourceNot checked yet

  Not checked in the free run.