Index

A

Activating protein-1 (AP-1) MAPK activity, 218 and NF-κB, 221

transcription factors, 222 Adrenomedullin (AM), 318

Advanced glycation end products (AGEs) and CTGF, PCDR

diabetic rats, treatment, 269 ECM components, 269–270 pericytes, 270

diabetic complications, role, 201 Age-related macular degeneration (AMD) choroidal neovascularization, 290

pegaptanib, 297 ranibizumab, 293

AGEs. See Advanced glycation end products A-kinase anchor protein 12 (APKAP12), 331 AM. See Adrenomedullin

AMD. See Age-related macular degeneration Angio-fibrotic switch, PDR

angiogenesis, 275–276 degree of fibrosis, 273–274 endothelial cells, 273 inhibition, 277

intravitreal inhibitors, 276 mean levels, 275 neovascularization, 274–275 PVR patients, 274

Angiogenesis description, 157–158

development and progression, DR, 211–212 growth factor alterations, 220

IGFBP-3, 238 NFs

FGF and EPO, 252 PEDF treatments, 250 VEGF, 252–253

VEGF, 234 Angiotensin II

activation, receptors, 312 neuroprotection, 312–313 RAS blockade, 312

AP-1. See Activating protein-1 APKAP12. See A-kinase anchor protein 12 Astrocyte end feet, 106–107

AZ. See Azurocidin Azurocidin (AZ)

and aprotinin, 110

BRB permeability, 114, 115 description, 110

inhibition

vascular leakage, 117 and VEGF, role, 117

injection, 114–115 β2-integrins expression, 109 role, VEGF-induced leakage

downstream effector, 116 downstream mediator, 115 intravitreal injection, 115–116

B

Basal lamina (BL) thickening knockout mice

CTGF protein expression, 272 retinal capillaries, 272, 273

PCDR, 268–270

TGF-β, 271–272 VEGF role, 270–271

Basement membrane, 264

BDNF. See Brain-derived neurotrophic factor Bevacizumab

chronic, diffuse edema, 298

Diabetic Retinopathy Clinical Research Network (DRCR), 297

endophthalmitis, 297–298 focal laser treatment, 298

Food and Drug Administration (FDA), 297 randomized trial, 298

reduction in central retinal thickness, 297 Blindness

developed and developing nations, 18 partial sight, 18

sensitivity analysis, 21–22 10-year incidence, 18

Blood–retinal barrier (BRB) alteration

acquisition, 60 macula, 59

retinal leakage mapping, 59 vitreous fluorometry, 59

Blood–retinal barrier (BRB) (cont.)

breakdown mechanisms (see BRB breakdown mechanisms)

functional unit, glial and endothelial cells, 327 physiological and diabetic conditions, 333, 335 retinal vascular barrier

astrocytes and Müller cells, 124 quadrants, 124

SSECKS, 124 vascular systems, 123

BL thickening. See Basal lamina thickening Brain-derived neurotrophic factor (BDNF)

dopaminergic amacrine cells, 251 expression, 317

BRB. See Blood–retinal barrier BRB breakdown mechanisms

anti-VEGF properties, natriuretic peptides (NP), 113–116

inner and outer

acute and chronic inflammation, 108 age-related diseases, 108 apolipoprotein E (apoE), 108 aprotinin, 110

AZ, 110 β2-integrins, 109 components, 106

leukocyte accumulation, 108–109 leukocyte adhesion, 109 neurovascular barrier, 106, 107 properties, 106–107

protein and fluid extravasation, 107 protein leakage assays, 108 selectins, 109

streptozotocin (STZ), 107 protective barriers

description, 105–106 structure, 105, 106

structural compromise neovascularization, 111 VEGF, 112–113

VAP-1, 111

vascular leakage, 105

C

Caspases

“executioner enzymes”, 191 immunoreactivity, 191–192

CCM. See Corneal confocal microscopy Cellular signaling

CNTF’s functions, 250

mechanisms (see Glucose-induced cellular signaling mechanisms)

Ciliary neurotrophic factor (CNTF) cytokines, 249

description, 317–318 functions, 250

retinal degeneration model, 250

CNTF. See Ciliary neurotrophic factor Color vision dysfunction

blue-yellow and blue-green, 71–72 FM 100 Hue Test, 73

hypotheses, 71 Combination treatment, laser

BCVA, 301

DRCR protocol, 302

ranibizumab and triamcinolone, 301 Complications, diabetic

HATs and HDACs, 222 MAPK pathway, 218

microvascular, polymorphisms, 217 O-linked glycosylation, 217

Connective tissue growth factor (CTGF) BL thickening

knockout mice, 272–273 PCDR, 268–270 TGF-β, 271–272

VEGF role, 270–271

ECM remodeling, PCDR, 262–264 mRNA levels, 268

ocular angiogenesis, 267 ocular fibrosis, 267 PDR, 273–277 structure and function

biological functions, 266 exons, 265–266 interactions, 266

wound healing, PDR, 264–265 Contrast sensitivity (CS)

neurodegenerative changes, 200 neuroretinal damage, 310

psychophysics (see Visual psychophysics, DR) Corneal confocal microscopy (CCM)

corneal sub-basal nerve plexus (CSNP), 46–48 diagnostic test, 46

fiber tortuosity (FT), 46, 48 focal plane, 46

nerve beadings, reduction, 46, 47 nerve fiber length (NFL), 46, 47 noncontact procedure, 46

number of beadings (NBe), 46, 47 number of branching (NBr), 46, 47 number of fibers (NF), 46, 47 Z-ring device, 46

Corneal diabetic neuropathy

CCM (see Corneal confocal microscopy) chronic disability, 45 electrophysiological tests, 45

long-term effects, 45 nerves

and diabetes, 48–50

subbasal corneal nerve plexus, 46 Corneal nerves and diabetes

abnormalities, 48 CSNP parameters, 49 hyperglycemia, 50

nerve bundles, 48 neurons, 50 neurotrophic stimuli, 49 pathological changes, 49 sensation, 48–49 stromal nerve trunks, 48

tortuosity stage, nerve plexus, 49 Corneal sub-basal nerve plexus (CSNP)

antioxidant therapy, 50 CCM, 47

five parameters, 46 mitochondria and glycogen, 48

CSNP. See Corneal sub-basal nerve plexus

D

Dark adaptation rainstorms, 8

shift, light to dark, 7

DCCT. See Diabetes Control and Complications Trial 1-DE. See 1-Dimensional electrophoresis

2-DE. See 2-Dimensional electrophoresis DHA. See Docosahexaenoic acid

Diabetes Control and Complications Trial (DCCT) β cell function

clinical benefit, 353 measurement, C-peptide, 352 “virtuous circle”, 352

benefits and risks, blood glucose factors and blockers, 342 HbA1c, 343

insulin regimen, 342–343 photographic evidence, 343

cardiovascular disease, 348 connecting peptide (C-peptide)

β cell function, 346 responders, 346

DKA, 345

DQOL, 348

DR progression, 19–20 epidemiology, 340–341 glycemia and macular edema

data, WESDR, 341

risk factor relationships, 341 treatment, 342

glycemic control regimen HbA1c level, 351, 352

hypoglycemia and weight gain, 350 insulin analogues, 351

intensive therapy, 350

limitations and glucose monitoring devices, 351 treatment, 351

hypoglycemia counterregulation, 352 intensive insulin therapy

beneficial effect, 343

risk reduction, prevention cohort, 344 ISLET cell transplantation, 356–357 metabolic memory, 348–349

morbidity, 340

pancreas transplantation, 353

prevalence and incidence, PDR, 349–350 reductions, HbA1c, 344–345

risk factors, hypoglycemia, 345 SPK transplantation, 353–355

treatment and HbA1c levels, 347–348 weight gain, 346

Diabetes Quality of Life Measure (DQOL), 348 Diabetic ketoacidosis (DKA), 345, 348, 351 Diabetic macular edema (DME)

bevacizumab, 297–299 clinical practice, 71

combination treatment, laser, 301–302 CS function, 76

2-DE-based proteomics, 181 duration and functional outcome, 97 efforts, 289–290

inhibition, VEGF, 175 management

antiangiogenic isoforms, 301 cytokine level, 301 focal/grid laser, 300 improvement, 300 interleukin-6 (IL-6), 301 leukocyte-mediated vascular

permeability, 300 microperimetry, 90

Mollon–Reffin “Minimalist” test, 72 pathogenesis

cataract surgery, 293 ETDRS, 292

fluorescein angiography, 290, 291 hyperglycemia, 290

hypoxia, 290

intravitreal triamcinolone, 293 laser, 292

optical coherence tomography (OCT), 290 PKC412, 292

placebo injection, 292 plasma leaks, 290

pegaptanib

neovascular AMD, 297 VEGF medication, 296 presentation and type, 70–71

quality of life

clinical trial data, 302 intensive treatments, 302 low-vision specialist, 303 NEI-VFQ-25, 302

proliferative diabetic retinopathy (PDR), 302

VTDR, 302 ranibizumab, 293–296 VEGF Trap-Eye, 299–300 vision loss, 173, 289 visual acuity, 83–84 vitreous hemorrhage, 289

370

Diabetic retina

eye management problem diabetes epidemic, 32 treatment focus, 32

vasculopathy and neuropathy, 32–33 multifocal electroretinogram (mfERG), 34–39 nonproliferative diabetic retinopathy

(NPDR), 31–32 patient care

assessment tools, 39–40 conventional perimetry, 40 “neuropathy”, 39 optometrists, 40

systemic markers, 40

visual acuity and foveal function “blue-cone” perimetry, 33 clinical and research tools, 34 mfERG, 33–34

neural dysfunction measures, 34 neural latency abnormalities, 34 predictive models, 34

“two-color threshold” technique, 33 Diabetic retinopathy (DR)

BRB

alteration, 59–60 complication, 246 capillary degeneration

description, 143

genetic modifications, 146, 148 interval, 147–148

metabolic control, molecular mechanisms, 146 metabolic memory, 148

molecular mechanisms, 146 nonuniform, 146

pharmacologic inhibition, 146, 147 retinal histopathology, 143, 144 retinal vasculature and neuronal retina

structure, 148–149

vascular nonperfusion, mechanisms, 144–146 VEGF, 143–144

changes, neurons and glia, 246 clinical trial design and management

drug, 64 ETDRS, 64

intravenous fluorescein, 65 MA turnover, 65 microthrombosis, 66 moderate NPDR, 65 significant visual loss, 64 slit-lamp examination, 65

description, 53

disease untreated, 21–22

formation and disappearance rates, MA, 55–59 health-care professionals and public, 20–21 history

BRB, abnormality, 55 endothelial cells, 55 microaneurysms (MA), 54

Index

nonproliferative diabetic retinopathy (NPDR), 54

pericyte damage, 54–55 prominent feature, 54 retinal changes, 54 retinal circulation, 55

hyperglycemia, 308

IGFBP-3 (see IGF-binding protein-3 (IGFBP-3))

incidence, 19 laser

photocoagulation, 308 treatment, 20

medical achievements, 14 microvascular circulation, 245, 246 multimodal macula mapping, 61 neurodegeneration

diabetic donors, 308 neuroretinal damage, 310 STZ, 309–311

neuronal and glial cell changes cytotoxic edema, 60

optical coherence tomography (OCT), 61 vascular endothelial damage, 60 WESDR data, 60

neurotoxic factors, neuropeptides, 311–318 neurotrophic drugs, 318–319

NF (see Neurotrophic factors) patient experience

altered vision, 7 blur, eyesight, 4 complications, 6–7 driving, 8

laser treatment, 5, 8

oxygen levels and blood vessels, 5 physician qualities, 6

transitions, light, 7 phenotypes, 61–64 photos, meaning

hydrant, 12, 13 unnatural, 12

prevalence

reports, North America, 18 worldwide reports, 18–19

prevention, 19–20

proteases (see Proteases, DR) public health problem

blindness and visual impairment, 18–19 prevalence, 18

qualitative study average age, 8

fear, blindness, 11–12 insulin, 11 microaneurysm, 9, 10 subhyaloid hemorrhage, 10

retinal capillary closure, 60 screening (see DR screening) symptomatic stage, 19

F

Farnsworth–Munsell 100-Hue Test (FM 100 Hue Test) color vision investigation, 73–75

description, 72

insulin-dependent diabetes mellitus (IDDM), 72 FGF. See Fibroblast growth factor

Fibroblast growth factor (FGF) angiogenesis, 252

retinal levels, βFGF, 252 Floaters

cause, 7

timing, appearance, 7–8

FM 100 Hue Test. See Farnsworth–Munsell 100-Hue Test

G

GDNF. See Glial cell-derived neurotrophic factor GH. See Growth hormone

Glial cell–derived cytokines and vascular integrity, DR BRB functional unit, 327

composition, BRB, 325–326 cytokines

APKAP12, 331

GDNF, 330–331 IL-6, 331 IL-1β, 330

TNF-α, 329–330 VEGF, 330

pathological progression, 326–327 retinoic acid (RA)

description, 331

GDNF expression, 331–332 promoter activity, GDNF, 332

RARα-mediated phenotypic transformation, 332 recombinant GDNF and RARα stimulants, 332

structural model, TJ, 325, 326 TJ

claudins, 329 description, 327–328

peripheral membrane proteins, 328 ZO-1 and 2, 329

Glial cell-derived neurotrophic factor (GDNF) BRB-forming capillary endothelial cells, 330–331 characterisation, 249

description, 317 signals, 317

Glucose-induced cellular signaling, DR cellular targets

EC dysfunction, 212–214 endothelial-matrix interactions, 214–215 endothelial-pericyte interactions, 214 pathogenetic mechanisms, 212

description, 211–212

development and progression, events, 211, 212 mechanisms

altered vasoactive factors, 215–216 growth factors, aberrant expression, 220

hexosamine pathway, 217 increased oxidative stress, 219–220 MAPK, 218

PKB and SGK-1, 218–219 PKC pathway, 218

polyol pathway, 216–217 protein glycation, 220 transcription factors, 221–222 transcription regulators, 222–223

Glucose-induced cellular signaling mechanisms growth factors, aberrant expression, 220 hexosamine pathway, 217

MAPK, 218 oxidative stress

hyperglycemia-induced, 219 lipoxygenase enzyme (LOX), 220 NADPH oxidase enzyme, 219–220 PARP, 220

PKB and SGK-1 inhibition, 218–219 isoforms role, 218

PKC pathway, 218 polyol pathway

aldose reductase (AR) inhibitor, 217 description, 216

enzymatic reactions, 216 metabolic/biochemical changes, 216, 217

protein glycation, 220 transcription factors

AP-1, 222 description, 221 NF-κB, 221–222

transcription regulators

acetylation and methylation, 222 histone and NF-κB response, 222–223 phosphorylation, 222

vasoactive factors NO synthases, 216

vasoconstriction and vasodilatory responses, 215–216

Glucose-induced oxidative stress, 219–220, 312 Glutamate

elevated levels, 312, 318 excitotoxicity, 311–312

Glutamate excitotoxicity description, 311–312 neurodegeneration, 201

Growth factors, 220 Growth hormone (GH)

and IGF pathway (see Growth hormone (GH)/ insulin-like growth factor (IGF) pathway)

inhibition, 313

Growth hormone (GH)/insulin-like growth factor (IGF) pathway

animal models normoglycemic/normoinsulinemic transgenic

mice, 236–237 OIR, 236

pro-angiogenic role, 236 IGFBP-3, as regulator

divergent cellular functions, 238 EPC recruitment, 238 inhibitory functions, 237

interventions and bioavailability, 237 retinal expression, 237–238

vitreal levels, 237 PDR

identification, factors, 234 IGFBPs role, 234–235

ROP

detrimental role, 235 severity, determination, 235

H

HATs. See Histone acetyltransferases HDACs. See Histone deacetylases Hexosamine pathway, 217

Histone acetyltransferases (HATs), 222 Histone deacetylases (HDACs), 222

I

ICAM-1. See Intracellular adhesion molecule 1 IGF. See Insulin-like growth factor IGF-binding protein-3 (IGFBP-3)

GH/IGF pathway

animal models, 236–237 PDR, 234–235

as regulator, 237–238 ROP, 235

inhibition, 239–240

laser treatments, 233–234 therapeutic interventions bolus injections, 238

correlation, serum and vitreal levels, 239 “early worsening”, 239

oxygen-induced vessel, 238–239 VEGF, 234

IGFBP-3. See IGF-binding protein-3 IL-6. See Interleukin-6

IL-1β. See Interleukin-1β Immunohistochemical analysis, 130–131 Inflammatory cytokines

APKAP12, 331

GDNF, 330–331 IL-6, 331 IL-1β, 330

TNF-α, 329–330 VEGF, 330

Insulin-dependent diabetes DCCT, 347

FM 100 Hue Test, 72 patient experience, 3–8 Insulin-like growth factor (IGF)

factor 1 (IGF-1), 252

intravitreal levels, 175–176

pathway, and GH (see Growth hormone (GH)/ insulin-like growth factor (IGF) pathway)

β2-Integrin

leukocyte adhesion, 109

ligation, endothelium, 110, 114, 115 neutrophils and monocytes, interaction, 109

Intensive insulin therapy beneficial effect, 343 cardiovascular disease, 348 hypoglycemia

counterregulation, 352 risk factors, 345

micro-and macrovascular disease, 347 risk reduction, prevention cohort, 344

Interleukin-6 (IL-6), 331 Interleukin-1β (IL-1β), 330

Intracellular adhesion molecule 1 (ICAM-1) AZ, 110

leukocyte, 109

leukocyte-induced BRB permeability, 114, 115 VEGF, 113

Islet cell transplantation, type 1 diabetes Edmonton protocol, 356

effects

chronic immunosuppression, 356 pancreas, 357

progression, 357

J

JAMs. See Junctional adhesion molecules Junctional adhesion molecules

(JAMs), 127–128

K

Kallikrein kinin system, 182, 183

L

Laser treatment and driving, 8 fear, 13–14

peripheral vision, 8 Leukocyte adhesion, 109 Liquefaction, vitreous, 174–175

Logarithm of the minimal angle of resolution (LogMAR), 70

LogMAR. See Logarithm of the minimal angle of resolution

M

MA. See Microaneurysm Macular edema

features, diabetic retinopathy, 53 OCT, 61

374

Macular recovery function description, 77

laser photocoagulation, 77, 83 retinal mechanism, 83

MAPK. See Mitogen-activated protein kinase Mass spectrometry

occludin phosphorylation, 131 vitreous proteomics

description, 179 spectral analysis, 179

workflow steps, 176, 177 Matrix metalloproteinases (MMPs)

angiogenesis, 160 cellular function, 160, 161

domain structure, 160, 161 groups, 160

significance, 162 synthesis, 160, 162 Metabolic memory, DCCT AGE formation, 349 hyperglycemia, 349

mitochondrial proteins, 349

mfERG. See Multifocal electroretinogram Microaneurysm (MA)

bleeding, 9, 10 bursting, 9

formation and disappearance rates CSME and non-CSME eyes, 58 cumulative number, 56 fluorescein angiography, 55, 57 formation rate, 56

foveal avascular zone (FAZ), 56 fundus-digitized images, 55 noninvasive color, 59

patients, metabolic control, 57 thrombotic phenomena, 57

laser, 292

plasma leakage, 290 turnover, 64

Mitogen-activated protein kinase (MAPK), 217 MMPs. See Matrix metalloproteinases Mollon–Reffin “Minimalist” test, 72, 74 Multifocal electroretinogram (mfERG)

adolescents and adult diabetes, 39 bipolar contact lens electrode, 35 logistic regression, 37

neural signals, 35 noninvasive technique, 34 predictive power, 35, 37

prophylactic therapeutics, 38–39

receiver operating characteristic (ROC), 37, 38 retinal area, zones, 38

scaled hexagons, 35, 36 sensitivity and specificity, 35, 37

type 1 vs. type 2, retinal function, 39 Multimodal macula mapping

developing methods, 61 diagnostic tools, 61 nonproliferative retinopathy, 62

Index

N

Natriuretic peptides (NP), anti-VEGF properties atrial natriuretic peptide (ANP), 114

AZ role, 115–116 inhibition, 113

permeability, leukocyte-induced, 114–115 pigment epithelium-derived factor (PEDF), 114

Neovascularization IGF-1

oxygen-induced retinal vessel, 238–239 receptor antagonist, 236

ROP phase, 235 proteases, 163–164

tissue inhibitor, MMPs, 164–166 VEGF, 290

Nerve fiber layer (NFL), 196 Nerve growth factor (NGF), 249 Neurodegeneration, DR

apoptosis, RGCs, 194 biochemical evidence

immunohistochemical analysis, 196–197 measurements, PSD95, 197

nNOS level, 197

synaptic proteins level, 197, 198 centrifugal axon abnormalities, 195–196 contrast sensitivity, 200

description, 189–190 diabetic donors, 308 downregulation, SST, 315 electrophysiological evidence

electroretinogram (ERG), 197–198 oscillatory potentials (OPs), 198–199 STR, 199

wave amplitude, 199 excitotoxicity, glutamate, 311–312 fundus examination, 203 histological evidence, apoptosis

“executioner enzymes”, caspases-3 and-7, 191–192

TUNEL, 190–191 neuroretinal damage, 310 NFL thickness, 196

optic nerve retrograde transport, 199 pathological changes, 190 postmortem retinas, 200

potential mechanisms AGEs role, 201

blood-retinal barrier, 200–201 calcium concentration, 202, 203 glutamate excitotoxicity, 201 growth factor signaling, 201, 203

psychophysical testing, 200 retina, morphological changes

inner plexiform (IPL) and nuclear layers (INL), 192, 193

layer thickness, reductions, 192–193 RGCs morphology, abnormalities

axon swelling and beading, 194–195 cell enlargement, 194

description, 194, 195 DiI use, 194

STZ, 309–311

surviving amacrine cells, reductions neurotransmitters, 193–194

tyrosine hydroxylase immunoreactivity, 193 Neuronal nitric oxide synthase (nNOS)

labeling, 193

neurons and vascular blood flow, 197 Neuropathy

neurosensory retina, 32 retinal complications, 39

Neuropeptides

angiotensin II, 312–313 BDNF, 317

CNTF and AM, 317–318 DHA and NPD1, 317

elevated levels, glutamate, 312, 318 Epo, 315–317

excitotoxicity, glutamate, 311–312 GDNF, 317

PEDF, 313 SST, 313–315

Neuroprotectin D1 (NPD1), 311, 317, 318 Neurotrophic factors (NFs)

BDNF, 251 CNTF, 249–250 diseases, 249 features, 249 FGF, 251–252

IGF-1 and EPO, 252 neuropeptides (see Neuropeptides) NGF and GDNF, 249

PEDF, 250 receptors, 247, 248 SERPINA3K, 251 VEGF, 252–253

NF-κB. See Nuclear factor-κB NFL. See Nerve fiber layer NFs. See Neurotrophic factors NGF. See Nerve growth factor

nNOS. See Neuronal nitric oxide synthase Non-enzymatic glycation, 220 Nonperfusion

cellular target, 212 sensitivity loss, 84 vascular

degeneration, 144 hemodynamics, 145 lumen invasion, 145 occlusions, 144

platelets, vasoocclusion, 145

VEGF, intravitreal administration, 146 white blood cells, vasoocclusion, 144–145

Nonproliferative diabetic retinopathy (NPDR), 31 NPD1. See Neuroprotectin D1

NPDR. See Nonproliferative diabetic retinopathy Nuclear factor-κB (NF-κB)

and AP-1, 222

MAPK activity, 218 PARP, 220

p65 expression, 222–223 transcription factors, 221

Nyctometry, 77, 83

O

OCT. See Optical coherence tomography OIR. See Oxygen-induced retinopathy Optical coherence tomography (OCT)

fluid accumulation image, 290, 291 measurements, 296, 300

Oxygen-induced retinopathy (OIR), 236

P

PAI. See Plasminogen activator inhibitors Pancreas transplantation, 353, 354, 356 PARP. See Poly (ADP-ribose) polymerase Pathogenesis, 148

PCDR. See Preclinical diabetic retinopathy PDGF. See Platelet-derived growth factor PDR. See Proliferative diabetic retinopathy PEDF. See Pigment epithelium-derived factor Pericytes

Akt activation, 133 barrier formation, 124 interactions, endothelial

(see Endothelial-pericyte interactions) PKC activity, 132

Perimetry description, 83

investigation, 84–88

kinetic and static automated, 83 SWAP and WWP, 84

visual acuity, 83–84 visual field testing, 83

Peripheral diabetic neuropathy, 45, 46 Phenotypes, DR

diabetes mellitus, 64 genetic factors, 64 HbA1C values, 62 hyperglycemia, 63, 64

patients observations, 62, 63 retinal thickness, 62

risk factors, 61 RLA-leaking, 62 visual acuity, 62

Pigment epithelium-derived factor (PEDF)

angiogenic inhibitor, 250 DR treatment, 313 inhibitors, angiogenesis, 313

intraperitoneal administration, 250 phyla, 313

VEGF, 250

PKA. See Protein kinase A PKB. See Protein kinase B

PKC. See Protein kinase C

Plasminogen activator inhibitors (PAI), 163 Platelet-derived growth factor (PDGF), 175 Polyol pathway, 216–217

Poly (ADP-ribose) polymerase (PARP), 220 Preclinical diabetic retinopathy (PCDR)

BL thickening, CTGF AGEs, 269–270 expression, 268–269

description, 261–262

rodent models, DR, 261–262 Proliferative diabetic retinopathy (PDR)

CTGF and VEGF angiogenesis, 275–276 degree of fibrosis, 273–274 endothelial cells, 273 inhibition, 277

intravitreal inhibitors, 276 mean levels, 275 neovascularization, 274–275 PVR patients, 274

1-DE-based proteomics, 182–184

2-DE-based proteomics, 181–182 GH/IGF pathway, 234–235 Lamoureux use, 302

PDGF, 175

protein concentration, 176–177 VEGF, 175

vision loss, 173 Proteases, DR

diabetic macular edema

inhibition, BRB prevention, 167–168 MMP-2 and MMP-9, 166–167 VE-cadherin staining, 167

retinal neovascularization

angiogenesis and matrix degradation, 164 angiogenesis inhibition, 165–166 hyperglycemic condition, 164

MMP activation, 163–164

TIMP-2 mRNA and protein levels, 164 tissue inhibitor, MMPs, 164–166 transcription factor, 164

uPAR expression, 164, 165 retinal vasculature

angiogenesis, 157–158 endogenous inhibitors, 163 extracellular proteases, 158–162 PAI, 163

vasculogenesis, 157 urokinase inhibitor, A6, 168

Protein glycation, 220

Protein kinase A (PKA), 218, 329 Protein kinase B (PKB), 218–219 Protein kinase C (PKC)

atypical (aPKC) isoforms, 133 classes, 132

classical isoforms and isozymes, 133 de novo synthesis, 132

isoforms role, 132 isozymes, BRB, 133, 134

membrane translocation and activation, 132 pathway, 218

Proteomics

vascular permeability, DR, 129

vitreous (see Vitreous proteomics, DR patients)

Q

Quality of life

and DME, 302–303 DQOL, 348 functional vision, 70 improvement, 6, 14

R

RA. See Retinoic acid Ranibizumab

AMD, 293, 295

anti-VEGF murine mono-clonal antibody, 293, 294 clinical trial, 293

foveal thickening, 293–294 MARINA and ANCHOR, 293 monoclonal antibody, 293 multicenter trial, 295

optimal dosing regimen, 296 reduction in macular edema, 296 RISE and RIDE phase III trials, 296 systemic side effects, 294

visual acuity, READ-2, 295, 296 RARα. See RA receptor-α

RA receptor-α (RARα)

phenotypic transformation, glial cells, 332, 334 stimulants, 332

trans-acting coactivator, 332 RAS. See Renin-angiotensin system Renin-angiotensin system (RAS)

angiotensin II, 312–313 blockade, 312

Retina

hemorrhages, 182, 183 proteins diffusion, 174

rhegmatogenous retinal detachment (RRD), 174 transferrin role, 175

vascular permeability (RVP), VEGF, 175 vitreous fluid, 176

Retinal ganglion cells (RGCs) abnormalities, 194

axon swelling and beading, 194–195 cell enlargement, 194

description, 194, 195 DiI use, 194

loss, 194

NFL thickness, 196 STR, 194, 195

Retinal leakage analyzer (RLA), 59, 61

Retinal neovascularization, proteases angiogenesis and matrix degradation, 164 angiogenesis inhibition

MMP inhibitors, 165–166 uPA/uPAR system, 166

hyperglycemic condition, 164 MMP activation, 163–164

TIMP-2 mRNA and protein levels, 164 transcription factor, 164

uPAR expression, 164, 165 Retinal pigment epithelium (RPE)

claudins expression, 126 controls, 123

tight junctions complex, 125 Retinal vascular endothelium, 54 Retinal vasculature

AGE formation, 269 integrity, 290

and neuronal retina structure, 148–149 proliferation, 246–247

proteases (see Proteases, DR) Retinoic acid (RA)

description, 331

GDNF expression, 331–332 promoter activity, GDNF, 332

RARα-mediated phenotypic transformation, 332 recombinant GDNF and RARα stimulants, 332

Retinoic X receptor (RXR), 331, 332 Retinopathy of prematurity (ROP), 235 Retinopathy progression

blood pressure, 66 fluorescein leakage, 56, 65 MA counting, 55

RGCs. See Retinal ganglion cells ROP. See Retinopathy of prematurity RPE. See Retinal pigment epithelium

S

Scanning laser ophthalmoscope (SLO) description, 89

microperimetry investigation, 89, 91–94 vs. MP-1 microperimeter, 89

Scotopic threshold response (STR), 199 Screening. See DR screening

Selectins, 109

Serum-and glucocorticoid-regulated kinase (SGK-1), 218–219

SGK-1. See Serum-and glucocorticoid-regulated kinase

Short-wavelength sensitive pathway (SWAP) description, 84

investigation, perimetry, 85–88 vs. WWP, 84

Simultaneous pancreas-kidney (SPK) transplantation immunosuppression, 353–354

NPDR PTA group, 355

scatter laser treatment, 354–355

worsening, retinopathy, 355

SLO. See Scanning laser ophthalmoscope Snellen chart, 70

Somatostatin (SST) downregulation, 315

functions, retinal homeostasis, 315 inhibitory actions, 313–314 neuroretina, 314–315

SPK transplantation. See Simultaneous pancreas-kidney transplantation

Src-suppressed C kinase substrate (SSECKS), 124 SSECKS. See Src-suppressed C kinase substrate SST. See Somatostatin

STR. See Scotopic threshold response Streptozotocin (STZ)

comparison, neurodegenerative features, 310–311 neurotoxic effect, 310, 318

RGCs, 310

St. Vincent declaration, 22 STZ. See Streptozotocin

SWAP. See Short-wavelength sensitive pathway

T

Terminal dUTP nick end labeling (TUNEL) description, 190

“executioner enzymes”, caspases-3 and-7, 191–192 immunoreactivity, caspase-3, 192

photoreceptors, 191 trypsin-digest approach, 190, 191

Tight junctions (TJ) claudins, 329

barrier formation, model, 126 description, 126

expression, 126–127 interactions, 126, 127

composition, 125 description, 327–328 formation, 125 JAMs

division, 127–128 role, 128

occludin

and claudin-5, localization, 128, 129 role, 128

sequence and structure, 128 peripheral membrane proteins, 328 tricellulin, 128

ZO, 125

ZO-1 and 2, 329

TIMPs. See Tissue inhibitors of metalloproteinases Tissue inhibitors of metalloproteinases (TIMPs), 163 TJ. See Tight junctions

TNF-α. See Tumor necrosis factor-α Tractional retinal detachment, 289 Transforming growth factor-beta (TGF-β)

and CTGF, BL thickening downstream effects, 271–272

Transforming growth factor-beta (cont.) drugs, 271

pericytes, 272 GDNF, 317 mRNA levels, 272

Tumor necrosis factor-α (TNF-α), 329–330 TUNEL. See Terminal dUTP nick end labeling

U

Ubiquitination, 131–132

UKPDS. See United Kingdom Prospective Diabetes Study

United Kingdom Prospective Diabetes Study (UKPDS), 19, 20

uPA. See Urokinase plasminogen activator Urokinase plasminogen activator (uPA)

angiogenesis and matrix degradation, 164 inhibition, retinal angiogenesis, 166 proteolytic activity, PAI, 163

secretion and activation, MMP, 163 uPA/uPAR system (see Extracellular proteases)

V

VA. See Visual acuity

VAP-1. See Vascular adhesion protein 1 Vascular adhesion protein 1 (VAP-1), 111 Vascular endothelial growth factor (VEGF)

capillary nonperfusion, 143–144 concanavalin A, 130–131 CTGF

ECM remodeling, 270–271

gene expression and protein levels, 270 ocular angiogenesis, 267

PDR, 274–277 cytokine, 113 description, 112 IGFBP-3 addition, 237 isoforms, 252–253

leukocyte-mediated breakdown, role, 330 levels, 175, 176

low levels, secretion, 253

“master switch”, angiogenesis, 234 members, 112

occludin, immunohistochemical analysis, 130 PDR and DME, mediator, 175

proliferation and migration, lymphatic endothelium, 112–113

proliferative neovascular vessels, 236–237 retinal neovascularization, role, 113 retinal vessel growth, 235

therapies, 253 Trap-Eye

antiangiogenic isoforms, 301 bevacizumab, 297

DME pathogenesis, 290 expression, 290

intravitreal injection, 300 PKC412, 290 ranibizumab, 296

recombinant fusion protein, 299 vascular permeability, 290

Vascular leakage

AZ inhibition, 117 AZ role, 115 description, 105

downstream effector, VEGF, 116 leukocyte mediators, 110 protein leakage assays, use, 108

Vascular permeability, DR activation, kallikrein, 130

changes, blood vessel and macular edema, 130 kallikrein/bradykinin system, 134

occludin phosphorylation

gene deletion and knockdown, 131 Ser490, 131

ubiquitination, 131–132 PKC

aPKC isoforms, 133 classes, 132

classical isoforms and isozymes, 133 de novo synthesis, 132

isoforms role, 132 isozymes, BRB, 133, 134

membrane translocation and activation, 132 VEGF-induced regulation, 130–131

Vasculogenesis, 157 Vasoocclusion

platelets, 145

white blood cells, 144–145

VEGF. See Vascular endothelial growth factor Vision Contrast Test System, 77

Visual acuity (VA) description, 70 ETDRS chart, 70–71 logMAR, 70 Snellen chart, 70

Visual impairment

macular degeneration, 18

national health and nutrition examination survey, 19

taking insulin, 18 working age group, 18

Visual psychophysics, DR acuity (VA), 70–71 color vision

abnormalities, 71–72 FM 100 Hue Test, 72 hypotheses, 71 investigation, 72–75 macular function, 71

Mollon–Reffin “Minimalist” test, 72

CS

acuity testing, 76 assessment procedure, 76

description, 72 investigation, 77–82 reductions, 76–77

spatial resolution defects, 76 Vision Contrast Test System, 77

description, 69–70

macular recovery function (nyctometry) description, 77

laser photocoagulation, 77, 83 retinal mechanism, 83

microperimetry description, 84

duration and functional outcome, DME, 97 fixation characteristics, 84

fixation pattern, 97 investigation, 90–97 macular disorders, 89 map, color fundus, 90, 97 MP-1 microperimeter, 89

retinal sensitivity, correlation, 90 SLO, 89

perimetry, 83–84 psychophysical test, 69

Vitreous

antiangiogenic activity, 313 EPO, 315

fluorometry, 59 growth factors, 220 level

CTGF, 273

IGF-1, 239 MMPs, 166–167

VEGF secretion, 253

proteomics (see Vitreous proteomics, DR patients)

Vitreous proteomics, DR patients acquisition

biological processes, 177–178 factors, 176

fluid, 176

protein concentration, 176–177 anatomy

collagen isoforms, concentrations, 174 gel-like composition, 174 liquefaction process, 174–175

characterization, 173–174 data analysis, 180

1-DE, 182–184

2-DE, 181–182 description, 176

direct functional analyses, 185 mass spectrometry, 179 molecule approach

IGF-I and IGF-binding proteins, 175–176 PDGF, 175

PDR and DME, 173 protein approach

transferrin, 175 VEGF, 175

sample pre-fractionation, 178–179 spectral analysis

label-free measurements, 180 parameters and thresholds, use, 179–180 Sequest and X!Tandem analyses, 179

workflow, steps, 176, 177

W

WESDR. See Wisconsin Epidemiologic Study of Diabetic Retinopathy

White-on-white perimetry (WWP) description, 84

investigation, 84–88 vs. SWAP, 84

Wisconsin Epidemiologic Study of Diabetic

Retinopathy (WESDR) blindness and visual impairment, 18 intensive insulin therapy, 340–341 retinal edema, 60

type 1 diabetes, 341 25-year progression, 18

Wound healing, PDR ECM production, 265 growth factors, 265

neovascularization and fibrosis, 265 VEGF, 264–265

WWP. See White-on-white perimetry

X

X!Tandem, 177, 179

Z

Zonula occludens (ZO) proteins, 125

ZO proteins. See Zonula occludens proteins