Abnormalities In Diabetic Retinopathy Research Articles

Detection of capillary abnormalities in early diabetic retinopathy using scanning laser ophthalmoscopy and optical coherence tomography combined with adaptive optics

This study tested if a high-resolution, multi-modal, multi-scale retinal imaging instrument can provide novel information about structural abnormalities in vivo. The study examined 11 patients with very mild to moderate non-proliferative diabetic retinopathy (NPDR) and 10 healthy subjects using fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), adaptive optics scanning laser ophthalmoscopy (AO-SLO), adaptive optics OCT and OCTA (AO-OCT(A)). Of 21 eyes of 11 patients, 11 had very mild NPDR, 8 had mild NPDR, 2 had moderate NPDR, and 1 had no retinopathy. Using AO-SLO, capillary looping, inflections and dilations were detected in 8 patients with very mild or mild NPDR, and microaneurysms containing hyperreflective granular elements were visible in 9 patients with mild or moderate NPDR. Most of the abnormalities were seen to be perfused in the corresponding OCTA scans while a few capillary loops appeared to be occluded or perfused at a non-detectable flow rate, possibly because of hypoperfusion. In one patient with moderate NPDR, non-perfused capillaries, also called ghost vessels, were identified by alignment of corresponding en face AO-OCT and AO-OCTA images. The combination of multiple non-invasive imaging methods could identify prominent microscopic abnormalities in diabetic retinopathy earlier and more detailed than conventional fundus imaging devices.

Hyperreflective Membrane at the Vitreoretinal Interface in Diabetic Macular Edema: A Finding in Ultra-High-Resolution Optical Coherence Tomography.

PurposeDetecting subtle vitreoretinal interface (VRI) findings, such as a posterior hyaloid membrane, is difficult with conventional retinal imaging. We compared ultra-high-resolution spectral domain optical coherence tomography (UHR-SD-OCT) with standard-resolution OCT (SD-OCT) for the imaging of VRI abnormalities in diabetic retinopathy (DR).MethodsThis prospective cross-sectional study included 113 consecutive patients (91 patients with diabetes and 22 healthy controls). The VRI was evaluated, and the results were compared between the conventional SD-OCT and UHR-SD-OCT images. VRI findings were also investigated before and after internal limiting membrane peeling during vitrectomy for proliferative DR.ResultsA total of 159 eyes (87.4%) of 91 patients with diabetes were analyzed. UHR-SD-OCT could detect a hyperreflective layer at the VRI, in which en face OCT showed a membrane-like structure, termed the hyperreflective membrane (HRMe). The preoperative HRMe could not be detected in all patients with proliferative DR who underwent internal limiting membrane peeling during vitrectomy. Although the HRMe did not correlate with the DR stage, eyes with diabetic macular edema (DME) (64.5%) showed a significant HRMe with UHR-SD-OCT more frequently than those without DME (35.8%) (P = 0.005).ConclusionsUHR-SD-OCT can detect the HRMe at the VRI in DR eyes, particularly in eyes with DME. The HRMe may present a thickened posterior hyaloid membrane that contributes to DME development.Translational RelevanceUHR-SD-OCT detects slight changes in the VRI in DR eyes. In the future, it may help to elucidate the mechanism of DME formation.

Detecting Diabetic Retinal Neuropathy Using Fundus Perimetry.

Fundus perimetry is a new technique for evaluating the light sense in the retina in a point-to-point manner. Light sense is fundamentally different from visual acuity, which measures the threshold for discriminating and perceiving two points or lines, called the minimum cognoscible. The quality of measurement of retinal sensitivity has dramatically increased in the last decade, and the use of fundus perimetry is now gaining popularity. The latest model of fundus perimetry, MP-3, can be used for a wide range of measurements and has an advanced eye tracking system. High background illumination enables accurate measurement of mesopic retail sensitivity. Recent investigations have shown that neuronal damage precedes vascular abnormalities in diabetic retinopathy. The loss of retinal function has also been reported prior to morphological changes in the retina. In this review, the importance of measuring retinal sensitivity to evaluate visual function in the early stages of diabetic retinopathy was discussed. The usefulness of retinal sensitivity as an outcome measure in clinical trials for treatment modalities is also presented. The importance of fundus perimetry is promising and should be considered by both diabetes researchers and clinical ophthalmologists.

Diabetic retinopathy: neurovascular disease requiring neuroprotective and regenerative therapies.

Diabetic retinopathy: neurovascular disease requiring neuroprotective and regenerative therapies.

The Pathogenesis and Therapeutic Approaches of Diabetic Neuropathy in the Retina.

Diabetic retinopathy is a major retinal disease and a leading cause of blindness in the world. Diabetic retinopathy is a neurovascular disease that is associated with disturbances of the interdependent relationship of cells composed of the neurovascular units, i.e., neurons, glial cells, and vascular cells. An impairment of these neurovascular units causes both neuronal and vascular abnormalities in diabetic retinopathy. More specifically, neuronal abnormalities including neuronal cell death and axon degeneration are irreversible changes that are directly related to the vision reduction in diabetic patients. Thus, establishment of neuroprotective and regenerative therapies for diabetic neuropathy in the retina is an emergent task for preventing the blindness of patients with diabetic retinopathy. This review focuses on the pathogenesis of the neuronal abnormalities in diabetic retina including glial abnormalities, neuronal cell death, and axon degeneration. The possible molecular cell death pathways and intrinsic survival and regenerative pathways are also described. In addition, therapeutic approaches for diabetic neuropathy in the retina both in vitro and in vivo are presented. This review should be helpful for providing clues to overcome the barriers for establishing neuroprotection and regeneration of diabetic neuropathy in the retina.

Fundus Image Analysis to Detect Abnormalities in Diabetic Retinopathy using Computer Aided Design Tools A Review

Diabetic retinopathy is becoming a major threat to visual loss in human beings. Many researchers are working to develop early detection techniques, which may reduce the risk of vision loss using image-processing techniques like image enhancement and segmentation. Improving the quality of medical images to detect the disease at an early stage is crucial for further medication. It is gaining more focus with automated techniques for machine learning. Filtering and morphological operators enhance image contrast and interested region can be extracted using segmentation techniques from the fundus image of the retina. For feature analysis the optical disk, localization of blood vessels and segmentation are very useful to observe the parameters like area, length and perimeter of blood vessels etc. Algorithms for this analysis include preprocessing, segmentation, feature extraction and classification. This paper tries to give a detailed review of various image-processing methods used in early detection of diabetic retinopathy and future insights to develop algorithms, which reduces clinician’s time for diagnosis and pathogenesis.

Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes.

Mitochondrial damage in the cells comprising inner (retinal endothelial cells) and outer (retinal pigment epithelium (RPE)) blood–retinal barriers (BRB) is known to precede the initial BRB breakdown and further histopathological abnormalities in diabetic retinopathy (DR). We previously demonstrated that activation of acid sphingomyelinase (ASM) is an important early event in the pathogenesis of DR, and recent studies have demonstrated that there is an intricate connection between ceramide and mitochondrial function. This study aimed to determine the role of ASM-dependent mitochondrial ceramide accumulation in diabetes-induced RPE cell damage. Mitochondria isolated from streptozotocin (STZ)-induced diabetic rat retinas (7 weeks duration) showed a 1.64 ± 0.29-fold increase in the ceramide-to-sphingomyelin ratio compared to controls. Conversely, the ceramide-to-sphingomyelin ratio was decreased in the mitochondria isolated from ASM-knockout mouse retinas compared to wild-type littermates, confirming the role of ASM in mitochondrial ceramide production. Cellular ceramide was elevated 2.67 ± 1.07-fold in RPE cells derived from diabetic donors compared to control donors, and these changes correlated with increased gene expression of IL-1β, IL-6, and ASM. Treatment of RPE cells derived from control donors with high glucose resulted in elevated ASM, vascular endothelial growth factor (VEGF), and intercellular adhesion molecule 1 (ICAM-1) mRNA. RPE from diabetic donors showed fragmented mitochondria and a 2.68 ± 0.66-fold decreased respiratory control ratio (RCR). Treatment of immortalized cell in vision research (ARPE-19) cells with high glucose resulted in a 25% ± 1.6% decrease in citrate synthase activity at 72 h. Inhibition of ASM with desipramine (15 μM, 1 h daily) abolished the decreases in metabolic functional parameters. Our results are consistent with diabetes-induced increase in mitochondrial ceramide through an ASM-dependent pathway leading to impaired mitochondrial function in the RPE cells of the retina.

The Oxygen Saturation in Vascular Abnormalities Depends on the Extent of Arteriovenous Shunting in Diabetic Retinopathy.

Diabetic retinopathy is characterized by disturbances in retinal blood flow mediated by capillary occlusion, intraretinal microvascular abnormalities (IRMAs), neovascularizations, and omega loops and reduplications. It is likely that the study of oxygen saturation in these abnormalities can provide knowledge about their role in the development of diabetic retinopathy. The oxygen saturation in IRMA vessels and venous loops and reduplications were studied in 40 diabetic patients with severe nonproliferative or proliferative diabetic retinopathy. The saturation values in the studied vascular abnormalities were compared to those of the larger retinal arterioles and venules. There was a similar oxygen saturation (mean ± SD) in IRMAs observed to connect arterioles with venules (78.6% ± 11.8%, n = 22) and IRMAs connecting venules with venules (79.2% ± 9.0%, n = 12; P > 0.999). The saturation in IRMAs was significantly lower (P < 0.0002) than in arterioles (97.4% ± 5.2%, n = 40) and significantly higher (P < 0.0001) than the saturation in omega loops and reduplications (54.2% ± 19.3%, n = 6), which in turn showed no significant difference from the saturation in the venules (61.8% ± 6.8%, n = 40, P = 0.4). The findings suggest that the oxygen saturation in vascular abnormalities in diabetic retinopathy depends on the extent of arteriovenous (A-V) shunting, with venous saturation due to no A-V shunting in venous loops and reduplications, and intermediate oxygen saturation due to moderate shunting in IRMAs. This may precede the development of neovascularizations with arterial oxygen saturation due to high A-V shunting.

Peripapillary Region Perfusion and Retinal Nerve Fiber Layer Thickness Abnormalities in Diabetic Retinopathy Assessed by OCT Angiography.

PurposeTo quantify peripapillary region perfusion and retinal nerve fiber layer (RNFL) thickness abnormalities in different stages of diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA).MethodsSeventy-two eyes of 72 patients with diabetes were included as follows: 23 with no DR (No DR), 24 with mild-to-moderate nonproliferative DR (mild DR), 25 with severe nonproliferative to proliferative DR (severe DR), and 26 age-matched healthy controls. All eyes underwent a 4.5 × 4.5-mm rectangle scan centered on the optic nerve head. Vessel densities and RNFL thickness for the peripapillary area were calculated.ResultsA statistically significant decrease in vessel density was found in the peripapillary region with increased DR severity (all P < 0.001). There were significant correlations between DR severity and vessel density in the peripapillary region (P < 0.001), but not between DR severity and RNFL thickness (P > 0.05). There was a significantly positive correlation between vessel density and RNFL thickness of the peripapillary region in the mild DR group (r = 0.726, P < 0.001) but not in the no DR group (r = 0.008, P = 0.973) or the severe DR group (r = 0.281, P = 0.173).ConclusionsVessel density in the peripapillary region correlated significantly with DR severity, decreasing with DR aggravation. There was no obvious correlation observed between RNFL thickness and DR severity.Translational RelevanceVessel density in the peripapillary region, assessed by OCTA technology, can be potentially useful for analyzing and monitoring retinal nerve changes in DR patients.

583-P: Increase in Mitochondrial Ceramide Contributes to Diabetes-Induced Retinal Endothelial Cell Damage

Mitochondrial damage precedes histopathological abnormalities in diabetic retinopathy (DR). Retinal endothelial cells (REC) have the highest level of Acid Sphingomyelinase (ASM) expression in the retina and the increase in ASM activity and ceramide production were shown to promote diabetes-induced pro-inflammatory and pro-apoptotic changes in the retina and REC. The role of diabetes-induced increase in ASM and ceramide production in mitochondrial damage in the retina and REC is not known. Retinal mitochondria from control, STZ-induced diabetic and ASM-/- rodent models, as well as Bovine REC (BREC) treated with diabetogenic conditions were isolated by differential centrifugation. Sphingolipids were analyzed by eSI-MS. Respiration was measured using a novel custom designed microrespirometer. Mitochondrial sphingomyelin (mSM) decreased (62 ± 1% compared to control 72.5 ± 7%, P&amp;lt;;0.05, n=3) and mitochondrial ceramide (mCer) increased (38 ± 4% compared to control 26.5 ± 6.5%, P&amp;lt;0.05, n=3 in 7 weeks diabetic rat retina. ASM-/- mouse model showed increased mSM (85.0 ± 6.7%) compared to wild type (77.0 ± 2.8%) and decreased mCer (11.5 ± 3.6%) compared to wild type (17.6 ± 3.6%, P&amp;lt;0.05, n=3), confirming that ASM is an essential contributor to mitochondrial ceramide regulation. Pre-treatment of BREC with an ASM inhibitor Desipramine revealed a 1.75-fold increase in maximal respiratory capacity compared to control cells. Diabetes results in decreased mitochondrial sphingomyelin and increased mitochondrial ceramide consistent with ASM-dependent ceramide production. Inhibition of ASM in BREC results in increased maximal, but not basal, respiratory rates. These results support the hypothesis that ASM activation and mitochondrial ceramide accumulation leads to inhibition of oxidative phosphorylation and REC damage in diabetic environment. Disclosure D. Pegouske: None. Y. Levitsky: None. S. Hammer: None. T.A. Lydic: None. A. Muchnik: None. D.A. Proshlyakov: None. J.V. Busik: None. Funding National Institutes of Health (R01EY028049, R01EY016077)

52-OR: Intrinsically Photosensitive Retinal Ganglion Cell Dysfunction in Diabetic Retinopathy Associates with Impaired Sleep and Circadian Rhythms

Background: Intrinsically photosensitive retinal ganglion cells (ipRGCs) control the pupillary light reflex (PLR) and synchronize sleep-wake cycles, melatonin secretion, and metabolic processes to the 24-h day. PLR abnormalities in diabetic retinopathy (DR) suggest ipRGC dysfunction. We explored whether ipRGC dysfunction in DR is associated with impaired sleep, circadian rhythms and metabolic functioning. Methods: Healthy controls (n=6), type 2 diabetes (T2D) without DR (n=8), or T2D with at least moderate DR (n=11) participated. PLR inferred ipRGC function, HbA1c, and nocturnal urinary 6-sulfatoxymelatonin (aMT6s/creatinine ratio) were measured. Sleep was recorded by 7-day actigraphy. Dim light melatonin onset (DLMO) was assessed by sampling saliva in the 7 hours before self-reported bedtime. Results: Mean age was 54.6±5.4 yr. The relative PLR was significantly smaller in T2D-DR (control vs. T2D-noDR vs. T2D-DR: 0.32(0.10) vs. 0.26 (0.09) vs. 0.13 (0.11), p=0.003). Nocturnal aMT6s [8.3 (3.1) vs. 14.6 (14.3) vs. 1.9 (2.1) ng/mg, p=0.001] was significantly lower in T2D-DR. Sleep was more disturbed in T2D-DR than others as reflected by higher wake time after sleep onset (p=0.024), higher fragmentation index (p=0.007) and lower sleep efficiency (p=0.030). HbA1c was similar between T2D groups. T2D-DR were more likely to have no detectable rise of salivary melatonin in the evening (normal 16% vs. DM-noDR 14% vs. DM-DR 67%, p=0.049). Smaller PLRs correlated with lower aMT6s (r=0.652, p=0.001). Among T2D, lower aMT6s and smaller PLR associated with lower sleep efficiency (p=0.029-0.046) and more fragmented sleep (p=0.028-0.066). There was no relationship between PLR or aMT6s with HbA1c in T2D. PLR was smaller in those without vs. with DMLO [0.11 (0.09) vs. 0.29 (0.09), p&amp;lt;0.001]. Conclusion: T2D with DR had dysregulated melatonin rhythm and disrupted sleep, which significantly correlated with the degree of ipRGC dysfunction. Disclosure S. Reutrakul: None. J.C. Park: None. F. Chau: None. T. Baynard: None. M. Priyadarshini: None. S. Crowley: None. J. McAnany: None. Funding University of Illinois at Chicago

VASCULAR ABNORMALITIES IN DIABETIC RETINOPATHY ASSESSED WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY WIDEFIELD IMAGING.

To detect vascular abnormalities in diabetic retinopathy using swept-source optical coherence tomography angiography (SS-OCTA) widefield images, and to compare the findings with color fundus photographs (CFPs) using Early Treatment Diabetic Retinopathy Study severity grading. 3 mm × 3 mm and 12 mm × 12 mm scans were acquired to cover 70° to 80° of the posterior pole using a 100-kHz SS-OCTA instrument. Two masked graders assessed the presence of vascular abnormalities on SS-OCTA and the Early Treatment Diabetic Retinopathy Study level on CFP. The grading results were then compared. A total of 120 diabetic eyes (60 patients) were imaged with the SS-OCTA instrument. Cohort 1 (91 eyes; SS-OCTA grading only) showed microaneurysms in 91% (n = 83), intraretinal microvascular abnormalities in 79% (n = 72), and neovascularization in 21% (n = 19) of cases. Cohort 2 (52 eyes; CFP grading compared with SS-OCTA) showed microaneurysms on CFP in 90% (n = 47) and on SS-OCTA in 96% (n = 50) of cases. Agreement in intraretinal microvascular abnormality detection was fair (k = 0.2). Swept-source optical coherence tomography angiography detected 50% of intraretinal microvascular abnormality cases (n = 26), which were missed on CFP. Agreement in detecting neovascularization was moderate (k = 0.5). Agreement in detection of diabetic retinopathy features on CFP and SS-OCTA varies depending on the vascular changes examined. Swept-source optical coherence tomography angiography shows a higher detection rate of intraretinal microvascular abnormalities (P = 0.039), compared with Early Treatment Diabetic Retinopathy Study grading.

Scan, dwell, decide: Strategies for detecting abnormalities in diabetic retinopathy.

Diabetic retinopathy (DR) is a disease which is widely diagnosed using (colour fundus) images. Efficiency and accuracy are critical in diagnosing DR as lack of timely intervention can lead to irreversible visual impairment. In this paper, we examine strategies for scrutinizing images which affect diagnostic performance of medical practitioners via an eye-tracking study. A total of 56 subjects with 0 to 18 years of experience participated in the study. Every subject was asked to detect DR from 40 images. The findings indicate that practitioners use mainly two types of strategies characterized by either higher dwell duration or longer track length. The main findings of the study are that higher dwell-based strategy led to higher average accuracy (> 85%) in diagnosis, irrespective of the expertise of practitioner; whereas, the average obtained accuracy with a long-track length-based strategy was dependent on the expertise of the practitioner. In the second part of the paper, we use the experimental findings to recommend a scanning strategy for fast and accurate diagnosis of DR that can be potentially used by image readers. This is derived by combining the eye-tracking gaze maps of medical experts in a novel manner based on a set of rules. This strategy requires scrutiny of images in a manner which is consistent with spatial preferences found in human perception in general and in the domain of fundus images in particular. The Levenshtein distance-based assessment of gaze patterns also establish the effectiveness of the derived scanning pattern and is thus recommended for image readers.

Analysis of Foveal Microvascular Abnormalities in Diabetic Retinopathy Using Optical Coherence Tomography Angiography with Projection Artifact Removal.

Purpose To analyze foveal microvascular abnormalities in different stages of diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA) with projection artifact removal (PAR). Methods We analyzed 93 eyes of 59 patients with diabetes—31 with no DR (no DR), 34 with mild to moderate nonproliferative DR (mild DR), and 28 with severe nonproliferative DR to proliferative DR (severe DR)—and 31 age-matched healthy controls. Sections measuring 3 × 3 mm2 centered on the fovea were obtained using OCTA. The area, perimeter, and acircularity index (AI) of the foveal avascular zone (FAZ), vessel density within a 300 μm wide region of the FAZ (FD-300), and parafoveal vessel density in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) were calculated using novel built-in software with PAR. Results There was no statistically significant difference in the FAZ area (p=0.162). There was a statistically significant difference in the FAZ perimeter (p=0.010) and the AI (p < 0.001) between the four groups. There was a correlation between the AI and the increasing severity of DR (p=0.010). Statistically significant decreases of vessel density in the FD-300, SCP, and DCP were observed (all p < 0.001). There was a difference in parafoveal vessel density in the DCP between the healthy control eyes and the eyes with diabetes without DR (p=0.027). There was a significant correlation between vessel density and increasing severity of DR (p < 0.001). Conclusion Compared with the FAZ area, AI allows a more helpful quantitative assessment of the changes in the FAZ. Vessel density determined using OCTA with PAR might be a useful parameter indicating the progression of DR. Parafoveal vessel density in the DCP after PAR might be a potential early biomarker of DR before appearance of clinically evident retinopathy and needs further investigation.

Volume-Rendered Optical Coherence Tomography of Diabetic Retinopathy Pilot Study

To investigate the retinal vascular findings and associated anatomic abnormalities in the central macula of eyes with diabetic retinopathy using volume-rendered angiographic and structural optical coherence tomography. Observational case series. In this retrospective study 25 eyes of 14 consecutive patients were imaged with optical coherence tomography (OCT) using split-spectrum amplitude decorrelation. The structural OCT data were segmented for cystoid spaces and integrated into the angiographic data for subsequent volume rendering. The opacity of various vascular layers could be decreased to improve visualization of deeper structures and the images could be rotated about 3 axes. The inner and deep vascular plexus were analyzed in relation to structural changes such as cystoid spaces and disorganization of the retinal inner layers. Retinal vascular flow abnormalities manifested by large flow voids in the inner vascular layer with retention of large vessels and confluent areas of flow loss in the deep plexus. Areas of cystoid edema were associated with topographically colocalizing flow voids in the deep vascular layer. In eyes with no edema isolated abnormalities of the deep plexus were associated with thinning of the inner nuclear layer and abnormalities of both layers were associated uniformly with the OCT findings of disorganization of the retinal inner layers. Widespread vascular abnormalities in diabetic retinopathy could be delineated along with the corresponding anatomic changes in the retina using volume-rendered angiographic and structural OCT. This method of imaging offers potential to improve visualization of vascular disorders of the eye.

Role of endoplasmic reticulum stress in the loss of retinal ganglion cells in diabetic retinopathy.

Endoplasmic reticulum stress is closely involved in the early stage of diabetic retinopathy. In the present study, a streptozotocin-induced diabetic animal model was given an intraperitoneal injection of tauroursodeoxycholic acid. Results from immunofluorescent co-localization experiments showed that both caspase-12 protein and c-Jun N-terminal kinase 1 phosphorylation levels significantly in-creased, which was associated with retinal ganglion cell death in diabetic retinas. The C/ERB mologous protein pathway directly contributed to glial reactivity, and was subsequently responsible for neuronal loss and vascular abnormalities in diabetic retinopathy. Our experimental findings dicate that endoplasmic reticulum stress plays an important role in diabetes-induced retinal neu-ronal loss and vascular abnormalities, and that inhibiting the activation of the endoplasmic reticulum stress pathway provides effective protection against diabetic retinopathy.

An Approach for the Detection of Vascular Abnormalities in Diabetic Retinopathy

Diabetic Retinopathy is a common complication of diabetes that is caused by changes in the blood vessels of the retina. The blood vessels in the retina get altered. Exudates are secreted, micro-aneurysms and hemorrhages occur in the retina. The appearance of these features represents the degree of severity of the disease. In this paper the proposed approach detects the presence of abnormalities in the retina using image processing techniques by applying morphological processing techniques to the fundus images to extract features such as blood vessels, micro aneurysms and exudates. These features are used for the detection of severity of Diabetic Retinopathy. It can quickly process a large number of fundus images obtained from mass screening to help reduce the cost, increase productivity and efficiency for ophthalmologists.

Review on Fundus Image Acquisition Techniques with Data base Reference to Retinal Abnormalities in Diabetic Retinopathy

Review on Fundus Image Acquisition Techniques with Data base Reference to Retinal Abnormalities in Diabetic Retinopathy

Complications of Diabetes Mellitus

The long-term complications of diabetes mellitus include retinopathy, nephropathy, and neuropathy. Diabetic retinopathy can result in loss of vision; nephropathy may lead to end-stage kidney disease (ESKD); and neuropathy poses the risk of foot ulcers, amputation, Charcot joints, sexual dysfunction, and potentially disabling dysfunction of the stomach, bowel, and bladder. Hyperglycemia sufficient to cause pathologic and functional changes in target tissues may be present for some time before clinical symptoms lead to a diagnosis of diabetes, especially in patients with type 2 diabetes. Diabetic patients are also at increased risk for atherosclerotic cardiovascular, peripheral vascular, and cerebrovascular disease. These conditions may be related to hyperglycemia, as well as to the hypertension and abnormal lipoprotein profiles that are often found in diabetic patients. Prevention of these complications is a major goal of current therapeutic policy and recommendations for all but transient forms of diabetes. This chapter describes the pathogenesis, screening, prevention, and treatment of diabetic complications, as well as the management of hyperglycemia in the hospitalized patient. Figures illustrate the pathways that link high blood glucose levels to microvascular and macrovascular complications; fundus abnormalities in diabetic retinopathy; the natural history of nephropathy in type 1 diabetes; cumulative incidence of first cardiovascular events, stroke, or death from cardiovascular disease in patients with type 1 diabetes; the effect of intensive glycemic therapy on the risk of myocardial infarction, major cardiovascular event, or cardiovascular death in patients with type 2 diabetes; and risk of death in patients with type 2 diabetes who receive intensive therapy of multiple risk factors or conventional therapy. Tables describe screening schedules for diabetic complications in adults, foot care recommendations for patients with diabetes, and comparison of major trials of intensive glucose control. This chapter has 238 references.

179 POSTER Phase I study of the novel anti-cancer drug PM00104 as a 1-hour weekly infusion resting every fourth week in patients with advanced solid tumors or lymphoma

The Eph receptor/ephrin system is a recently discovered regulator of vascular development during embryogenesis. Activation of EphA2, one of the Eph receptors, reportedly suppresses cell proliferation and adhesion in a wide range of cell types, including vascular endothelial cells. Vascular endothelial growth factor (VEGF) plays a primary role in both pathological angiogenesis and abnormal vascular leakage in diabetic retinopathy. In the study described herein, we demonstrated that EphA2 stimulation by ephrinA1 in cultured bovine retinal endothelial cells inhibits VEGF-induced VEGFR2 receptor phosphorylation and its downstream signaling cascades, including PKC (protein kinase C)-ERK (extracellular signal-regulated kinase) 1/2 and Akt. This inhibition resulted in the reduction of VEGF-induced angiogenic cell activity, including migration, tube formation, and cellular proliferation. These inhibitory effects were further confirmed in animal models. Intraocular injection of ephrinA1 suppressed ischemic retinal neovascularization in a dose-dependent manner in a mouse model. At a dose of 125 ng/eye, the inhibition was 36.0 ± 14.9% (P < 0.001). EphrinA1 also inhibited VEGF-induced retinal vascular permeability in a rat model by 46.0 ± 10.0% (P < 0.05). These findings suggest a novel therapeutic potential for EphA2/ephrinA1 in the treatment of neovascularization and vasopermeability abnormalities in diabetic retinopathy.