Treatment Of Proliferative Diabetic Retinopathy Research Articles

Identification of chemokines and growth factors in proliferative diabetic retinopathy vitreous.

Associations were investigated between levels of chemokines and growth factors in the vitreous and proliferative diabetic retinopathy (PDR). Enrolled were 58 patients (58 eyes) requiring pars plana vitrectomy (PPV), with PDR (n = 32, none with traction retinal detachment) or not (non-PDR). In the latter, 16 had macular hole (MH) and 10 had epiretinal membrane (ERM). With a multiplex bead immunoassay, levels of 11 chemokines and growth factors were measured from the undiluted vitreous sample from each patient. In the non-PDR eyes, the levels of the 11 chemokines and growth factors tested were similar between patients with MH and those with ERM. However, the levels of all 11 were significantly higher in the PDR eyes relative to the non-PDR; CCL17, CCL19, and TGFβ3 were markedly upregulated and have not been investigated in PDR previously. The significantly higher levels of CCL4 and CCL11 in PDR contradict the results of previous reports. Based on Spearman's nonparametric test, moderate-to-strong correlations were found between VEGF and other mediators. Our results indicate that these chemokines and growth factors could be candidates for research into targeted therapies applied either singly or in combination with anti-VEGF drugs for the treatment of PDR.

VEGF Secreted by Hypoxic Müller Cells Induces MMP-2 Expression and Activity in Endothelial Cells to Promote Retinal Neovascularization in Proliferative Diabetic Retinopathy

In proliferative diabetic retinopathy (PDR), retinal ischemia promotes neovascularization (NV), which can lead to profound vision loss in diabetic patients. Treatment for PDR, panretinal photocoagulation, is inherently destructive and has significant visual consequences. Therapies targeting vascular endothelial growth factor (VEGF) have transformed the treatment of diabetic eye disease but have proven inadequate for treating NV, prompting exploration for additional therapeutic options for PDR patients. In this regard, extracellular proteolysis is an early and sustained activity strictly required for NV. Extracellular proteolysis in NV is facilitated by the dysregulated activity of matrix metalloproteinases (MMPs). Here, we set out to better understand the regulation of MMPs by ischemia in PDR. We demonstrate that accumulation of hypoxia-inducible factor-1α in Müller cells induces the expression of VEGF, which, in turn, promotes increased MMP-2 expression and activity in neighboring endothelial cells (ECs). MMP-2 expression was detected in ECs in retinal NV tissue from PDR patients, whereas MMP-2 protein levels were elevated in the aqueous of PDR patients compared with controls. Our findings demonstrate a complex interplay among hypoxic Müller cells, secreted angiogenic factors, and neighboring ECs in the regulation of MMP-2 in retinal NV and identify MMP-2 as a target for the treatment of PDR.

Identification of VEGF-Independent Cytokines in Proliferative Diabetic Retinopathy Vitreous

To identify inflammatory cytokines significantly elevated and independent of VEGF levels in the vitreous of proliferative diabetic retinopathy (PDR) patients that may serve as novel diagnostic factors or therapeutic targets. Thirty-nine cytokines and chemokines were measured from the vitreous of 72 patients undergoing vitrectomy (29 controls and 43 PDR) via a magnetic bead-based immunoassay. Patient information, including sex, age, history of smoking, cancer diagnosis and treatment, and presence of diabetes and hypertension were also collected. Univariate and multivariate logistic regression analyses were performed to assess the association of cytokine concentrations and patient demographics with disease. Nineteen cytokines were significantly elevated in the vitreous of PDR patients compared with controls, including five novel cytokines that have not previously been associated with PDR: sCD40L, GM-CSF, IFNα2, IL-12p40, and MCP-3. Sixteen cytokines were found to be statistically independent of VEGF. Of these, 14 show a statistically significant interaction with VEGF, while two do not. With regards to patient demographics, age and hypertension were statistically significant risk factors with the odds of disease decreasing with increasing age and increasing 3-fold for hypertensive patients. This is the first report of a comprehensive multiplex analysis to identify novel VEGF-independent cytokines associated with PDR. Of the 39 inflammatory cytokines tested, 16 are predictive of disease risk, independent of VEGF levels. These PDR-associated cytokines represent potential targets in the treatment of PDR, both in conjunction with anti-VEGF therapy, as well as for patients that are nonresponders to such therapy.

Intravitreal bevacizumab for proliferative diabetic retinopathy with new dense vitreous hemorrhage after full panretinal photocoagulation

To evaluate the efficacy and safety of intravitreal bevacizumab (IVB) injections for the treatment of proliferative diabetic retinopathy (PDR) with new dense vitreous hemorrhage (VH) after previous full panretinal photocoagulation (PRP). Prospective study of consecutive PDR with prior complete PRP patients, who presented with new dense VH, were treated with IVB injection. Complete ophthalmic examination and/or ocular ultrasonography were performed at baseline and 1, 6, and 12 weeks and 6, 9, and 12 months after the first injection. Reinjection was done in non-clearing and recurrent VH. Eighteen eyes of 18 patients, mean age 47.7 ± 12.69 years were included. In all, 14 (77.78%) patients had type 2 diabetes mellitus. Systemic hypertension and dyslipidemia were the most common systemic diseases. All cases were phakic eye with previous complete PRP. Patients received 1.6 ± 0.42 intravitreal injections over a 12-month period. VH cleared completely in 7 (38.89%), 9 (50%), and 13 (72.22%) eyes after 6 weeks, 6 months, and 12 months, respectively. Re-bleeding, however, occurred in 10 (56%) eyes during the follow-up period, and 5 (28%) eyes still had residual VH at the last visit. Statistically significant visual gain was observed in 9 (50%) eyes. Unfortunately, 2 (11%) eyes had severe visual loss because of the tractional retinal detachment (TRD). Mild ocular complication was detected in one patient. IVB injection had good efficacy and safety for treatment of new VH in patients with PDR and prior complete PRP. This procedure may be especially relevant for diabetic patients at high-risk for surgical intervention.

Aqueous humour levels of placental growth factor in diabetic retinopathy

Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, is a proangiogenic factor, originally isolated from human placenta (Maglione et al. 1991). Lines of evidence have elucidated that PlGF participates in angiogenic process not only directly by signalling via VEGF receptor (VEGFR)-1 but indirectly by amplifying VEGF-driven angiogenesis through regulation of inter- and intramolecular cross-talk between VEGFR-1 and VEGFR-2 (Autiero et al. 2003). Therefore, it is plausible that PlGF, synergistically with VEGF, plays a role in the development of ocular angiogenic disorders. So far, it has been reported that vitreous level of PlGF is increased in patients with proliferative diabetic retinopathy (PDR) compared with nondiabetic patients (Yamashita et al. 1999). Herein, we report the elevation of PlGF levels in aqueous humour from patients with diabetic retinopathy (DR), particularly in patients with neovascular glaucoma (NVG) due to DR. Aqueous humour samples were collected from 20 eyes of 20 patients with DR, including six with diabetic macular edema (DME) (mean age, 58.3 ± 3.5 years old), eight with PDR (50.5 ± 6.6 years old) and six with NVG (64.8 ± 2.3 years old). For control, samples were obtained from eight eyes of eight age-matched patients without diabetes, that is, epiretinal membrane or senile cataract (68.0 ± 3.3 years old). Protein level of PlGF was measured using ELISA kits for human PlGF (R&D Systems, Minneapolis, MN, USA), according to the manufacturer's protocol. Aqueous levels of PlGF were significantly elevated in patients with DME (24.5 ± 4.8 pg/ml) and PDR (52.8 ± 27.1 pg/ml), whereas PlGF was undetectable in patients without diabetic ocular complication (Fig. 1A). Notably, PlGF levels in aqueous samples of NVG group showed approximately 10-fold increase (577.4 ± 277.2 pg/ml) compared with those of PDR group (p < 0.05, Mann–Whitney U-test) (Fig. 1B). Yamashita et al. (1999) have reported intravitreal concentrations of PlGF to be significantly elevated in patients with PDR (360 ± 272 pg/ml) than those with nonischaemic retinal diseases. The results of the present study are in accordance with previous data showing that PlGF was not detectable in aqueous humour samples from non-DR patients; however, in patients with DME and PDR, PlGF level was elevated. Furthermore, the aqueous level of PlGF was markedly elevated in NVG group. The current data indicate that aqueous level of PlGF is related to the severity of diabetic ocular complication and accumulation of proangiogenic factor PlGF in anterior chamber aggravates iris neovascularization in DR. The previous and current data have shown that aqueous level of PlGF is lower in comparison with the vitreous levels of PlGF, suggesting that PlGF is secreted in the posterior segment of the eye and diffuses through the vitreous cavity to the anterior chamber during DR progression. It has been shown that retinal pigment epithelial (RPE) cells can produce PlGF in response to growth factors such as bone morphogenetic protein-4, known as a participant in ocular angiogenesis (Hollborn et al. 2006). In addition, it was reported that cultured optic nerve head astrocytes secreted PlGF (Kernt et al. 2010). Therefore, it is possible that RPE and glial cells are cellular sources of PlGF in the diabetic retina. Further investigation is necessary to elucidate the mechanism(s) by which PlGF is elevated in the anterior chamber in case with DR. Therefore, PlGF may be an attractive molecular target in the prevention of pathological angiogenesis, and the current data suggest that targeting PlGF may prove beneficial in the treatment of PDR, particularly in case with NVG.

New Laser Technologies for Diabetic Retinopathy

Diabetic retinopathy is a leading cause of severe visual impairment for adults worldwide. Vision loss from systemic diabetes usually occurs secondary to macular edema or from de novo proliferation from the retinal vasculature. The Diabetic Retinopathy Study (DRS) established that panretinal photocoagulation (PRP) reduces the risk of severe vision loss from proliferative disease by >50 % and, thus, PRP has become the gold standard in the treatment of proliferative disease. The Early Treatment of DRS expanded the use of laser photocoagulation to clinically significant macular edema. Advances in laser technology have led to the development of semi-automated lasers, including pattern scanning laser (PASCAL®, Topcon) and fully automated lasers, such as the navigating lasers (NAVILAS®, OD/OS), that aim to deliver faster, safer, more accurate, and less painful treatment of diabetic eye disease and other retinal conditions. Sublethal phototherapy with subthreshold diode micropulsed laser treatment for macular edema has led to a paradigm shift in our understanding of retinal photocoagulation by demonstrating similar efficacy with less collateral damage. Here, we review the current data on laser treatment of diabetic retinopathy with an emphasis on understanding the new laser photocoagulation technologies for treatment of proliferative diabetic retinopathy and clinically significant diabetic macular edema.

Sudden visual loss in the untreated eye of a patient with neovascular glaucoma following an intravitreal bevacizumab injection: A case report

The current study presents the case of a patient with a rare adverse event characterized by sudden vision loss in the untreated eye following an intravitreal injection of bevacizumab for neovascular glaucoma (NVG). The patient was diagnosed with NVG refractory to Ahmed glaucoma valve implantation and a vitreous hemorrhage in the right eye, which was treated with 1.25 mg intravitreal bevacizumab. Ten days after the bevacizumab injection, the left eye exhibited sudden visual loss. The patient’s best-corrected visual acuity (BCVA) decreased from 80 to 25 letters [Early Treatment Diabetic Retinopathy Study (ETDRS) chart]. A fundus examination revealed a swollen optic disk with unclear boundaries, retinal hemorrhages and thinning retinal vessels. Fundus fluorescein angiography (FA) identified hyperfluorescence in the optic disk and an enlarged foveal avascular zone. The visual field revealed quadrantal defects that confirmed the diagnosis of anterior ischemic optic neuropathy associated with ischemic maculopathy. Six months later, following medical treatment, the patient’s BCVA was increased to 44 letters. However, a clinical examination found neovessels with one papilla disk (PD) above the disk. Laser photocoagulation treatment was administered immediately. The area of neovessels above the disk was reduced to 1/4 PD at the last follow-up. In conclusion, although intravitreal anti-vascular endothelial growth factor (Bevacizumab) is an effective treatment for neovascular ocular diseases, its adverse effects must be taken into consideration for the treatment of NVG. Photocoagulation remains an effective treatment for proliferative diabetic retinopathy.

Diabetic retinopathy: pathogenesis, clinical grading, management and future developments

Decades of research into the pathophysiology and management of diabetic retinopathy have revolutionized our understanding of the disease process. Diabetic retinopathy is now more accurately defined as a neurovascular rather than a microvascular disease as neurodegenerative disease precedes and coexists with microvascular changes. However, the complexities of the pathways involved in different stages of disease severity continue to remain a challenging issue for drug discovery. Currently, laser photocoagulation is the mainstay of treatment for proliferative diabetic retinopathy, but is gradually being superseded for diabetic macular oedema. However, it is destructive and at best results in a gradual but modest improvement in vision in the long term. So, diabetic retinopathy remains the most prevalent cause of visual impairment in the working-age population despite established screening programmes, early diagnosis and treatment of the condition. The recent discovery of inhibitors of vascular endothelial growth factor is revolutionizing the management of diabetic retinopathy, particularly diabetic macular oedema. However, not all patients respond to anti-vascular endothelial growth factor agents, reinforcing the fact that diabetic retinopathy is a multifactorial disease. Studies are still required to improve our understanding of how retinal structure correlates with visual function. It is hoped that these will lead to better characterization of the disease phenotype based on treatment responses to different agents and allow an algorithm to be developed that will guide the management of diabetic retinopathy and diabetic macular oedema at different stages of severity.

Computer-aided Diagnosis of Proliferative Diabetic Retinopathy via Modeling of the Major Temporal Arcade in Retinal Fundus Images

Monitoring the openness of the major temporal arcade (MTA) and how it changes over time could facilitate diagnosis and treatment of proliferative diabetic retinopathy (PDR). We present methods for user-guided semiautomated modeling and measurement of the openness of the MTA based on Gabor filters for the detection of retinal vessels, morphological image processing, and a form of the generalized Hough transform for the detection of parabolas. The methods, implemented via a graphical user interface, were tested with retinal fundus images of 11 normal individuals and 11 patients with PDR in the present pilot study on potential clinical application. A method of arcade angle measurement was used for comparative analysis. The results using the openness parameters of single- and dual-parabolic models as well as the arcade angle measurements indicate areas under the receiver operating characteristics of A z = 0.87, 0.82, and 0.80, respectively. The proposed methods are expected to facilitate quantitative analysis of the architecture of the MTA, as well as assist in detection and diagnosis of PDR.

Comparative Study between Panretinal Photocoagulation versus Combined Panretinal Photocoagulation and Intravitreal Bevacizumab Injection in Treatment of Proliferative Diabetic Retinopathy

Comparative Study between Panretinal Photocoagulation versus Combined Panretinal Photocoagulation and Intravitreal Bevacizumab Injection in Treatment of Proliferative Diabetic Retinopathy

Evolving strategies in the management of diabetic retinopathy

Diabetic retinopathy (DR), the most common long-term complication of diabetes mellitus, remains one of the leading causes of blindness worldwide. Tight glycemic and blood pressure control has been shown to significantly decrease the risk of development as well as the progression of retinopathy and represents the cornerstone of medical management of DR. The two most threatening complications of DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Focal/grid photocoagulation and panretinal photocoagulation are standard treatments for both DME and PDR, respectively. Focal/grid photocoagulation is a better treatment than intravitreal triamcinolone acetonide in eyes with DME. Currently, most experts consider combination focal/grid laser therapy and pharmacotherapy with intravitreal antivascular endothelial growth factor agents in patients with center-involving DME. Combination therapy reduces the frequency of injections needed to control edema. Vitrectomy with removal of the posterior hyaloid seems to be effective in eyes with persistent diffuse DME, particularly in eyes with associated vitreomacular traction. Emerging therapies include fenofibrate, ruboxistaurin, renin-angiotensin system blockers, peroxisome proliferator-activated receptor gamma agonists, pharmacologic vitreolysis, and islet cell transplantation.

Posterior Subtenon Triamcinolone Acetonide in Gas-filled Eyes as an Adjunctive Treatment for Complicated Proliferative Diabetic Retinopathy

PurposeTo evaluate the effect of adjunctive subtenon injection of triamcinolone acetonide (TA) in gas-filled eyes after vitrectomy for complicated proliferative diabetic retinopathy (PDR).MethodsThis nonrandomized comparative study included 27 patients (27 eyes) who underwent pars plana vitrectomy and gas tamponade for treatment of PDR with tractional or combined tractional-rhegmatogenous retinal detachment and who received subtenon injection of TA (40 mg) at the end of surgery. The study group was compared with the control group (29 eyes), which was matched with the study group for preoperative and intraoperative parameters, but underwent pars plana vitrectomy and gas tamponade without a subtenon injection of TA.ResultsRetinal reattachments without reoperation were achieved in 25 eyes (92.6%) and 26 eyes (89.7%) at 6 months (p = 1.000) in the study and control groups, respectively. The study group and the control group did not differ significantly in the frequency of postoperative proliferative vitreoretinopathy, retinal redetachment rate, reoperation rate, macular pucker formation, postoperative vitreous hemorrhage, gain in visual acuity, intraocular pressure, and intraocular inflammation (p > 0.05).ConclusionsThe clinical results of pars plana vitrectomy for complicated PDR are not improved significantly by an adjunctive subtenon TA injection in gas-filled eyes.

Spurious Elevation of Glucose Concentration during Administration of High Dose of Ascorbic Acid in a Patient with Type 2 Diabetes on Hemodialysis

We describe herein a case of life-threatening hypoglycemia due to spurious elevation of glucose concentration during the administration of ascorbic acid in a type 2 diabetic patient. A 31-year-old female was admitted for proliferative diabetic retinopathy treatment and prescribed high dose ascorbic acid. During hospitalization, she suddenly lost her consciousness and her glucose concentration was 291 mg/dL, measured using self-monitoring blood glucose (SMBG) device, while venous blood glucose concentration was 12 mg/dL. After intravenous injection of 50% glucose solution, the patient became alert. We reasoned that glucose measurement by SMBG device was interfered by ascorbic acid. Physicians should be aware of this interference; high dose ascorbic acid may cause spurious elevation of glucose concentration when measuring with SMBG devices.

IVTA as Adjunctive Treatment to PRP and MPC for PDR and Macular Edema: A Meta-Analysis

BackgroundTo quantify the effect of a combination treatment of intravitreal triamcinolone acetonide (IVTA) injection, panretinal photocoagulation (PRP), and macular photocoagulation (MPC) in patients with proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME).Methodology/Principal FindingsWe conducted a meta-analysis and searched for reports concerning IVTA injection combined with PRP for the treatment of PDR and DME using Medline, EMbase, Web of Science, the Cochrane Library, and Google according to Cochrane evaluation guidelines. The quality of the reports was evaluated using the Jadad score. Only four studies were ultimately included in this meta-analysis and the fixed-effects model was used. Treatment with IVTA injection combined with PRP and MPC significantly improved BCVA (p<0.001) from one to six months, compared with PRP and MPC alone. There was a statistically significant mean difference in central macular thickness (CMT), at the one-month follow-up (p<0.001). No evidence of publication bias was present. There was a low level of heterogeneity in this group of studies.Conclusions/SignificanceThis meta-analysis indicates that IVTA injection combined with PRP and MPC results in an improvement of BCVA, and CMT reduction in patients with PDR and DME.

Comparison of 23G and 20G vitrectomy for treatment of proliferative diabetic retinopathy

Objective To compare the outcomes of 23G and 20G vitrectomy in treatment of proliferative diabetic retinopathy (PDR).Methods This was a prospective randomized study.One hundred twenty six patients (142 eyes) suffering from PDR with symptoms requiring vitrectomy were randomly divided into 20G vitrectomy group (66 patients,74 eyes) and 23G vitrectomy group (60 patients,68 eyes).Visual acuity,intraocular pressures,indirect ophthalmoscopy,B-scan ultrasound,tear film break up time (BUT),Schirmer I test (S I T),astigmatic power and the astigmatic axial at 6 mm area of anterior and posterior corneal surface were observed and measured before surgery.The follow-up period was 15.0 and 12.5 months separately in 20G and 23G groups.Intraoperative complications,operation time,postoperative visual acuity,intraocular pressure,postoperative complications,re-operation,and postoperative ocular conditions including changes of astigmatic power and the astigmatic axial measurements were analyzed.Results At last follow-up,there was 49 eyes (66.2％) and 47 eyes (69.1％) with visual acuity ≥0.05 in 20G and 23G groups.Comparing visual acuity ≥0.05,there was no statistical difference between the groups (x2=0.14,P＞0.05).The eyes suffering from iatrogenic injuries were 18 (24.3％) and seven (10.3％).There was obvious difference in iatrogenic injury between the two groups (x2=4.81,P＜0.05).The mean surgical times were (69.0±8.2) and (51.0±6.3) minutes in 20G and 23G group,which was significantly different (t=3.65,P＜0.05).The postoperative third day,hypotony was detected in three (4.1％) and 11 eyes (14.7％) in 20G and 23G group,which was a significantly different (x2=5.85,P＜0.05).Postoperatively high intraocular pressures were not significantly different between the two groups (x2=2.54,P＞0.05).There were 24 (32.4％) and 14 eyes (20.6％) in 20G and 23G group.There were significant differences in BUT,S I T,astigmatic power and the astigmatic axial measurements compared with those preoperatively at the first month after operation (t=3.35,4.12,-3.12,-3.22; P＜0.05),but no significant differences in them at the third and sixth month after operation (third month:t =0.45,0.98,-2.12,-1.02; P＞0.05,and the sixth month:t=0.95,1.48,-1.02,-2.11; P＞0.05).In 23G group,there were no significant differences in BUT,S I T,astigmatic power and the astigmatic axial measurements compared with those preoperatively at the first,third and sixth month after operation (first month:t=l.21,1.46,-2.32,-1.61; P＞0.05,third month:t=1.45,2.21,-2.19,-1.89; P＞0.05,and sixth month:t=1.92,1.25,-1.76,-2.35; P＞0.05).Conclusion 23G vitrectomy is a safe and effective treatment for PDR with shorter surgery time,fewer surgical complications and postoperative ocular surface changes. Key words: Diabetic retinopathy/surgery; Vitrectomy; Comparative study

Comparative analysis of different surgery methods in treatment of proliferative diabetic retinopathy patients with cataract

Objective To compare the effects of two treatmnent methods in the treatment of proliferative diabetic retinopathy (PDR) patients with cataract.Methods 79 PDR patients with cataract,according to the different surgical methods were divided into:phacoemulsification with lensectomy of 41 cases(52 eyes) in Group A and crystal resection with lensectomy of 38 cases(48 eyes) in Group B.The changes of eye pressure,iris neovascularization (INV),fundus fluorescein angiography were observed.Results The visual acuity increased in 42cases (80.0％)postoperative in group A,which was significantly higher than that of group B [ 30 cases(62.5％ ) ] (x2 =4.26,P ＜ 0.05) ;The incidence of INN was 3.8 ％ in Group A,which was significantly lower than that of Group B (12.5％ )( x2=4.02,P ＜ 0.05 ) ;The macular edema and postoperative fundus fluorescein angiography showed no significant difference in two groups ( x2 =2.02,2.58,all P ＞ 0.05 ).Conclusion The effect of phacoemulsification with vitrectomy for the treatment of PDR with cataract was superior to the posterior lens removal of vitrectomy surgery. Key words: Phacoemusification ; Proliferative, diabetic retinophathy ; Vitrectomy; Lensectomy; Iris neovascularization

Role of Intravitreal Inflammatory Cytokines and Angiogenic Factors in Proliferative Diabetic Retinopathy

Objective: Inflammatory reaction has been shown to involve the progress of type 2 (non-insulin-dependent) diabetes. We, therefore, examined the effects of inflammatory cytokines and angiogenic factors in the pathogenesis of proliferative diabetic retinopathy (PDR) in type 2 diabetes.Patients and methods: Vitreous fluid samples were obtained by vitrectomy from 62 eyes of PDR patients with type 2 diabetes and from 20 eyes of age-matched non-diabetic patients. The concentrations of interleukin 1 beta (IL1B), IL6, IL8, IL10, chemokine (C-C motif) ligand 2 (CCL2), endothelin 1 (EDN1), vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF) in the vitreous samples were measured by enzyme-linked immunosorbent assay (ELISA).Results: The concentrations of LI1B, IL6, IL8, CCL2, EDN1, VEGF, and TNF in the vitreous samples were considerably higher in PDR patients in comparison with the controls. However, the level of IL10 in PDR patients was similar to that obtained in the controls. Analysis of the correlations of the studied factors revealed the correlation of VEGF and IL6, VEGF and EDN1, IL8 and CCL2, and EDN1 and TNF in PDR patients. In addition, a significant positive correlation was observed between vitreous TNF as well as EDN1 and serum HbA1c levels in PDR patients.Conclusions: The inflammatory cytokines and angiogenic factors IL1B, IL6, IL8, CCL2, EDN1, VEGF, and TNF are increased in the vitreous of PDR patients without an increase in IL-10. These results add support to the role of inflammatory cytokines and angiogenic factors in the genesis of PDR. Understanding the implication of these cytokines may provide diagnostic tools and therapeutic targets for treatment and prevention of PDR.

Ranibizumab in patients with dense cataract and proliferative diabetic retinopathy with rubeosis

Background:To evaluate the safety of ranibizumab as a surgical adjunct during cataract surgery in patients with proliferative diabetic retinopathy (PDR) with rubeosis, and to evaluate the efficacy and adverse effects of ranibizumab in treating PDR with rubeosis.Materials and Methods:Three intravitreal injections of 0.5 mg ranibizumab were administered on day-1, months-1 and -2 with cataract surgery 6-16 days after first injection. Retreatments with ranibizumab injections and pan-retinal photocoagulation (PRP) were given if recurrence or persistence of PDR was noted between months-3 and -11. Safety observation visits occurred at months-12, -18 and -24. Primary end points were incidence and severity of adverse events (AEs) that were related to both cataract surgery and treatment of PDR with rubeosis through month -12.Results:Of six patients screened, four (mean age 61.3 years) were enrolled. No AEs were noted with either cataract surgery or treatment of PDR. Neovascularization of iris (NVI) promptly regressed by 4 days after first ranibizumab injection, prior to cataract surgery in three of four patients (one had significantly regressed NVI by post-injection day-3 visit); NVI was not noted in any patient at 2 weeks after first ranibizumab injection. Recurrence of rubeosis or NVA after 3 monthly injections was not observed in any. At month-12, PDR was not present when assessed clinically and by fluorescein angiogram (FA). Only one patient developed neovascularization of disc and neovascularization elsewhere and required retreatments at months-5 and -9.Conclusions:Multiple intravitreal injections of ranibizumab may be a safe, effective treatment adjunct for PDR and diabetes-related rubeosis.

The use of antivascular endothelial growth factor agents in the perioperative period in diabetic vitrectomy

Pars plana vitrectomy is an established surgical method for the treatment of proliferative diabetic retinopathy and its complications. Anti-vascular endothelial growth factor agents suppress vascular proliferation and may be used as pharmacological adjuvants to reduce the incidence of postoperative hemorrhage in the vitreous cavity and to facilitate the surgical approach. We conducted an electronic search to identify prospective randomized controlled trials looking at the use of —perioperative vascular endothelial growth factor suppression in diabetic patients undergoing vitrectomy. We found six prospective randomized trials with only one being double-masked. We present a summary of the findings. Four studies suggest that the use of perioperative, anti-vascular endothelial growth factor agents facilitate vitrectomy surgery, but only one study supports their use to reduce the chances of early postoperative vitreous bleeding. Two studies did not find a significant benefit for their use before surgery to reduce the recurrence of vitreous hemorrhage in proliferative diabetic retinopathy. More randomized double blinded studies with a larger number of patients are needed to establish a clear recommendation regarding the use of these agents. Those studies should factor in the use of endo-tamponade with gas or silicone oil following vitrectomy.

Characterisation of the vitreous proteome in proliferative diabetic retinopathy

BackgroundDiabetes can lead to serious microvascular complications such as proliferative diabetic retinopathy (PDR), which results in severe vision loss. The diabetes-induced alterations in the vitreous protein composition in diabetic patients with PDR may be responsible for the presence of PDR. The vitreous humour can be utilised in a variety of studies aimed toward the discovery of new targets for the treatment or prevention of PDR and the identification of novel disease mechanisms. The aim of this study was to compare the protein profile of vitreous humour from diabetic patients with PDR with that of vitreous humour from normal human eyes donated for corneal transplant.ResultsVitreous humour from type 2 diabetic patients with PDR (n = 10) and from normal human eyes donated for corneal transplant (n = 10) were studied. The comparative proteomic analysis was performed using two-dimensional fluorescence difference gel electrophoresis (2-D DIGE). Differentially produced proteins (abundance ratio > 2 or < -2, p < 0.01) were identified by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and MALDI-TOF tandem mass spectrometry. A total of 1242 protein spots were detected on the 2-D master gel of the samples, and 57 spots that exhibited statistically significant variations were successfully identified. The spots corresponded to peptide fragments of 29 proteins, including 8 proteins that increased and 21 proteins that decreased in PDR. Excluding the serum proteins from minor vitreous haemorrhage, 19 proteins were found to be differentially produced in PDR patients compared with normal subjects; 6 of these proteins have never been reported to be differentially expressed in PDR vitreous: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH 1), tubulin alpha-1B chain, gamma-enolase, cytosolic acyl coenzyme A thioester hydrolase, malate dehydrogenase and phosphatidylethanolamine-binding protein 1 (PEBP 1). The differential production of pigment epithelium-derived factor (PEDF) and clusterin was confirmed by Western blot analysis.ConclusionsThese data provide an in-depth analysis of the human vitreous proteome and reveal protein alterations that are possibly involved in the pathogenesis of PDR. Further investigation of these special proteins may provide potential new targets for the treatment or the prevention of PDR.