Subthreshold micropulse diode laser treatment in diabetic macular edema: biological impact, therapeutic effects, and safety.

PURPOSE: To introduce the treatment of diabetic macular edema (DME) with subthreshold micropulse diode laser (SMPL), to summarize the biological impact, therapeutic effects, and safety of this treatment, and to discuss the response to DME when SMPL is combined with anti-vascular endothelial growth factor (anti-VEGF) or steroid. METHODS: The literature search was performed on the PubMed database, with a selection of English-language articles published from 2000 to 2023 with the following combinations of search terms: diabetes macular (o) edema, micropulse laser or subthreshold micropulse laser, anti-vascular endothelial growth factor, and steroid. RESULTS: SMPL is a popular, invisible retinal laser phototherapy that is inexpensive, safe, and effective in the treatment of DME. It can selectively target the retinal pigment epithelium, reduce the expression of pro-inflammatory factors, promote the absorption of macular edema, and exert a similar and lasting clinical effect to traditional lasers. No significant difference was found in the therapeutic effects of SMPL between different wavelengths. However, HbA1c level and pretreatment central macular thickness (CMT) may affect the therapeutic outcomes of SMPL. CONCLUSION: SMPL has a slow onset and produces lasting clinical effects similar to conventional photocoagulation. It has been reported that SMPL combined with the intravitreal anti-VEGF injection can significantly reduce the number of injections without influencing the therapeutic effect, which is essential for clinical applications and research. Although 577 nm SMPL is widely used clinically, there are no standardized protocols for SMPL. Additionally, some important problems regarding the treatment of SMPL require further discussion and exploration.

Association Between Atrial Fibrillation and Diabetes-Related Complications: A Nationwide Cohort Study.

OBJECTIVE: This study aimed to investigate the associations between concurrent atrial fibrillation and diabetes-related complications among patients with diabetes. RESEARCH DESIGN AND METHODS: This nationwide observational cohort study used the health checkup database from the Korean National Health Insurance Service. Patients diagnosed with diabetes who underwent health checkups between 2009 and 2012 were investigated. The patients with atrial fibrillation were matched in a 1:5 ratio with those without atrial fibrillation using propensity scores. Study outcomes included macrovascular, microvascular (diabetic retinopathy and diabetic nephropathy), and diabetic foot complications. The risks of clinical outcomes were measured using hazard ratios (HRs) with 95% CIs. RESULTS: A total of 65,760 patients with diabetes were analyzed (54,800 without atrial fibrillation and 10,960 with atrial fibrillation). After well-balanced propensity score matching, atrial fibrillation was associated with significantly higher risks of macrovascular complications (HR 1.12, 95% CI 1.09-1.16), diabetic nephropathy (HR 1.23, 95% CI 1.16-1.30), and diabetic foot complications (HR 1.13, 95% CI 1.09-1.17) compared with no atrial fibrillation, while the risk of diabetic retinopathy was comparable (HR 0.99, 95% CI 0.96-1.03). Patients with atrial fibrillation had a significantly higher risk of diabetic foot amputation (HR 4.12, 95% CI 1.98-8.56). CONCLUSIONS: Among patients with diabetes, concurrent atrial fibrillation was associated with increased risks for diabetes-related macrovascular complications, diabetic nephropathy, and diabetic foot. Such patients require holistic management to reduce the risk of adverse outcomes.

Role of Vitamin B12 Deficiency and Hyperhomocysteinemia in Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the most important causes of preventable visual impairment among patients of working age and leading cause of blindness. Deficiency of vitamin B12 and folate has been associated with increased serum homocysteine (Hcy) levels. This study was done to find out the role of vitamin B12 and Hyperhomocysteine (HHcy) in Diabetic retinopathy. The present study is a hospital-based case-control study conducted during over a period of 12 months from January 2019 to December 2019 study conducted in the Department of Ophthalmology at BIRDEM General Hospital, Dhaka, Bangladesh consisting of 100 Type 2 DM patients either with or without retinopathy (DR, n=50 and DNR, n=50, respectively). Subjects with Type 2 DM with and without retinopathy were recruited from patients attending in the department of Ophthalmology at BIRDEM General Hospital, Dhaka and were matched for duration of diabetes. Diabetes subjects on nutritional supplements for the last 6 months and those with a history of nephropathy (based standard renal function tests) and complications other than DR were excluded. Homocysteine (Hcy) levels were inversely related (p<0.05) with Diabetes patients with retinopathy. Vitamin B12 also significant correlated with Diabetes patients with retinopathy. A statistically significant negative linear relationship was found between serum homocysteine and vitamin B12 levels (Pearson r = -0.918, p=0.001) Diabetes patients with retinopathy. Vitamin B12 significantly correlated with diabetes retinopathy and homocysteine levels were inversely related with diabetes patients with retinopathy.

Onion ring sign on spectral domain optical coherence tomography in diabetic macular edema: Its evolution and outcomes.

PURPOSE: To report evolution and outcomes of hyperreflective crystalline deposit (HCD) on optical coherence tomography (OCT) in diabetic maculopathy (DM). METHODS: Patients with DM showing HCD on OCT for the first time between June 2017 and May 2021 were included in the study. Demographic, ophthalmic and OCT features were documented and analysed. Factors leading to the development of HCD and its effect on the functional outcome were analysed and described in this study. RESULTS: Sixty cases of HCD were identified in 45 (males -33; females - 12) patients for the first-time during the defined study period. Mean age of the eligible patients was 61.53 ± 8.19 years. Average duration of diabetes was 13.82 ± 7.38 years. Mean visual acuity of these patients was 0.902 ± 0.438 logMAR units (Snellen equivalent = 20/160). Patients with HCD showed subretinal hard exudates, were on anti-cholesterol medications (n = 36, 80%) and showed reduced visual acuity (20/160) if the HCD involved the fovea. The median time taken for the development of HCD was 28 months. Mean follow-up duration of the study was 26.19 ± 27.98 months. Persistence of HCD in all cases (n = 42, 100%) was noted at the last follow-up visit. CONCLUSION: Horizontal, single or multi-layered HCDs on OCT in DM represent intraretinal or subretinal cholesterol crystal precipitates evolving from the hard exudates identical to the "onion ring sign" seen in neovascular AMD. HCDs or CCs depict deranged lipid metabolism, chronic vascular leakage and can lead to substantial visual impairment if the fovea gets involved.

The effect of palm oil-derived tocotrienol-rich fraction in preserving normal retinal vascular diameter in streptozotocin-induced diabetic rats.

PURPOSE: Angiogenesis in diabetic retinopathy (DR) is associated with increased retinal expression of angiopoietin-2 (Ang-2) and protein kinase C (PKC). Tocotrienol-rich fraction (TRF) has been shown to reduce the expression vascular endothelial growth factor (VEGF) in several experimental models. However, its effect against other angiogenic markers such as Ang-2 and PKC in rat model of diabetes remains unknown. Therefore, we investigated the effect of TRF on the retinal vascular changes and Ang-2 and PKC expressions in rats with streptozotocin (STZ)-induced DR. METHODS: Sprague-Dawley rats were divided into normal control rats (N) which received vehicle, and diabetic rats which either received vehicle (DV) or 100 mg/kg of TRF (DT). Diabetes was induced with intraperitoneal injection of STZ (60 mg/kg body weight). Treatments were given orally, once daily, for 12 weeks after confirmation of hyperglycaemia. Fundus photographs were captured at baseline, 6- and 12-week post-STZ injection and average diameter of retinal veins and arteries were measured. At 12-week post-STZ injection, rats were euthanised, and retinae were collected for measurement of Ang-2 and PKC gene and protein expressions. RESULTS: Retinal venous and arterial diameters were significantly greater in DV compared to DT at week 12 post-STZ injection (p < 0.001 and < 0.05, respectively). The vessel diameter measurements in DT were comparable to N and this effect of TRF was associated with significantly lower Ang-2 and PKC gene and protein expressions compared to DV. CONCLUSION: Oral TRF reduces the expression of retinal angiogenic markers and preserves the retinal vascular diameter of rats with STZ-induced DR.

Principales fitoquímicos con potencial terapéutico en el tratamiento de la retinopatía diabética con fitofármacos / Major Phytochemicals with Therapeutic Potential in the Treatment of Diabetic Retinopathy

La diabetes mellitus tipo 2 representa uno de los principales problemas de salud pública a nivel mundial hoy en día. Entre las principales complicaciones generadas por esta enfermedad se encuentra la retinopatía diabética, la cual puede conducir a pérdida de la visión de manera permanente, por lo que investigaciones sobre tratamientos para esta patología van en aumento. Es por esto que tratamientos en base a químicos obtenidos de plantas medicinales están siendo ampliamente investigados debido a que podrían proveer una alternativa más segura, de menor costo y menor toxicidad que la medicina estándar para el tratamiento de esta patología ocular de alta incidencia mundial. El objetivo de este estudio fue identificar los principales fitoquímicos con potencial para ser usados como tratamiento de la retinopatía diabética. Para lograr este cometido se llevó a cabo una revisión de la literatura publicada entre el enero 2017 y de junio 2021 utilizando las bases de datos WOS, PubMed y Scopus en inglés y español, con el fin de recopilar evidencia científica actualizada sobre el uso y efectos de fitoquímicos en la retinopatía diabética. Diversas familias de fitoquímicos útiles fueron identificadas, entre estas las más comunes fueron las de origen fenólico, aunque menos comunes también se encontraron carotenoides, terpenos y preparaciones constituidas por varias especies de plantas y fitoquímicos. Sus mecanismos de acción también fueron identificados, siendo los más comunes la supresión de la neovascularización mediada por VEGF, la protección y restauración de la barrera hematorretinal, la reducción en la actividad de las especies reactivas del oxígeno y el efecto antiinflamatorio. Dada la evidencia respecto a la utilidad de los fitoquímicos para el tratamiento de la retinopatía diabética, mayores investigaciones deben ser realizadas(AU)

Type 2 diabetes mellitus represents one of the main public health problems worldwide today. Among the main complications generated by this disease is diabetic retinopathy, which can lead to permanent vision loss. For this reason, research on treatments for this pathology is increasing. This is why treatments based on chemicals obtained from medicinal plants are widely investigated as they could provide a safer, less costly and less toxic alternative to standard medicine for the treatment of this eye disease of high incidence worldwide. The aim of this study was to identify the main phytochemicals with potential to be used as treatment for diabetic retinopathy. In order to achieve this purpose, a review of the literature published between January 2017 and June 2021 was conducted using the WOS, PUBMED and Scopus databases in English and Spanish, in order to compile updated scientific evidence on the use and impact of phytochemicals in diabetic retinopathy. Several families of useful phytochemicals were identified. Among these, the most common were those of phenolic origin, although less common were also found carotenoids, terpenes and blends consisting of various plant species and phytochemicals. Their mechanisms of action were also identified, the most common being suppression of vascular endothelial growth factor-mediated neovascularization, protection and restoration of the blood-retinal barrier, reduction in reactive oxygen species activity and anti-inflammatory effect. Given the evidence regarding the usefulness of phytochemicals for the treatment of diabetic retinopathy, further research should be conducted(AU)

Acute effect of hyperbaric oxygen therapy on macular and choroidal thickness in patients with type 2 diabetes and diabetic foot ulcers: Optical coherence tomography based study.

PURPOSE: To evaluate the acute effect of hyperbaric oxygen therapy (HBOT) on central macular thickness (CMT) and choroidal thickness (CT) in patients with type 2 diabetes mellitus (T2D) undergoing HBOT due to diabetic foot ulcer (DFU). METHODS: For this cross-sectional study, patients with T2D were recruited between May 2019 and June 2020. Only eyes with non-proliferative or no diabetic retinopathy (DR) were included. CMT and subfoveal, nasal, and temporal CT values measured by spectral-domain optical coherence tomography (Nidek RS-3000 Advance, Aichi, Japan) before and 45 minutes after the first HBOT session were compared between eyes with and without DR and between patients receiving only insulin therapy (group 1) or insulin+oral antidiabetic (group 2). Relationships between post-HBOT change in these parameters and age, sex, HbA1c level, and DR presence and stage were evaluated. RESULTS: The study included 49 eyes of 26 patients with DFU (aged 43-75 years). Post-HBOT changes in CMT and CT were not significant or associated with age, gender, DR stage, or HbA1c level (p > 0.05). Eyes with DR had significantly higher pre- and post-HBOT CMT, nasal CT, and temporal CT values compared to non-DR eyes. Nasal CT increased significantly after HBOT in eyes with DR. Group 1 (28 eyes, 15 patients) had higher pre-HBOT mean subfoveal CT and greater post-HBOT change in subfoveal CT than group 2 (21 eyes, 11 patients). CONCLUSIONS: HBOT was not associated with acute changes in CMT or CT in patients with T2D, although an increase in nasal CT was observed in eyes with DR.

The effect of vitamin D supplementation on the outcome of treatment with bevacizumab in diabetic macular edema: a randomized clinical trial.

PURPOSE: Concomitant vitamin D deficiency (VDD) is speculated to aggravate diabetic macular edema (DME). We aimed to determine the effect of hypovitaminosis D correction on the outcome of treatment with intravitreal bevacizumab (IVB) in DME eyes. METHODS: In this randomized clinical trial, 83 eyes of 83 patients with DME were recruited and divided into three groups: normal vitamin D levels + IVB administration (Group 1), vitamin D insufficient/deficient + IVB administration (Group 2), and vitamin D insufficient/deficient + IVB administration + oral vitamin D supplementation (Group 3). Participants were followed for 6 months after the intervention. Visual (corrected distance visual acuity, CDVA) and anatomical (central macular thickness, CMT) outcomes of intervention were evaluated 1, 3, and 6 months after three monthly loading doses of IVB were given. Serum vitamin D levels were measured 1 and 6 months after the third IVB administration. RESULTS: A total of 29, 26, and 28 eyes were enrolled in groups 1, 2, and 3, respectively. In months 1, 3, and 6, after the three basic loading doses of IVB, visual acuity and CMT improved in all three groups, but improvements (both functional and anatomical) in groups 1 and 3 in month 6 were more significant than in group 2 (mean CDVA LogMAR changes: - 0.18 ± 0.03, - 0.14 ± 0.05, and - 0.2 ± 0.06; mean CMT reductions: - 82.24 ± 11.43, - 66.62 ± 14.34, and - 86.14 ± 18.36, in groups 1, 2, and 3, respectively; p < 0.001). The mean number of IVB injections during follow-up was 5.33 (range 4-7), which did not differ between the groups. CONCLUSION: Correction of vitamin D deficiency in DME patients with type 2 diabetes and vitamin D deficiency, in addition to IVB injections, may play a role in improving CDVA and CMT. However, this beneficial effect seems to be delayed by several months. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), IRCT20200407046978N1, registered on April 11, 2020, retrospectively registered ( https://en.irct.ir/trial/46999 ).

Efficacy and safety of vitamin supplements with resveratrol in diabetic macular edema: Long-term results of a comparative study.

PURPOSE: To investigate the adjunct efficacy and safety of vitamin supplements, including resveratrol, in patients with diabetic macular edema (DME) treated with intravitreal anti-vascular endothelial factor (anti-VEGF) agents. METHODS: Participants in this prospective study were 45 patients with DME, who were treated with either intravitreal anti-VEGF injections (n = 23, Group I) or with combination of intravitreal anti-VEGF injections and vitamin supplements, including resveratrol (n = 22, Group II). All patients underwent visual acuity measurement, slit-lamp examination and spectral domain-optical coherence tomography (SD-OCT) at baseline and monthly after the loading phase of three-monthly anti-VEGF injections, following a PRN protocol. RESULTS: There was a statistically significant improvement in visual acuity in both groups at month 12 compared to baseline, although the mean change in visual acuity did not differ between the two groups (p = 0.183). Accordingly, there was a statistically significant decrease in central retinal thickness in both groups at month 12 compared to baseline, while the mean difference in central retinal thickness was significantly greater in the "combination" group. The mean number of intravitreal anti-VEGF injection was less in Group II (6.45 ± 1.12 in Group II vs. 7.39 ± 1.31 in Group I, p = 0.018). CONCLUSIONS: Vitamin supplements with resveratrol was found to be an effective adjunct to intravitreal anti-VEGF injections in patients with DME, offering better anatomic restoration with less injections at the 12-month follow-up.

A Randomized Trial of Photobiomodulation Therapy for Center-Involved Diabetic Macular Edema with Good Visual Acuity (Protocol AE).

PURPOSE: To determine if treatment with a photobiomodulation (PBM) device results in greater improvement in central subfield thickness (CST) than placebo in eyes with center-involved diabetic macular edema (CI-DME) and good vision. DESIGN: Phase 2 randomized clinical trial. PARTICIPANTS: Participants had CI-DME and visual acuity (VA) 20/25 or better in the study eye and were recruited from 23 clinical sites in the United States. METHODS: One eye of each participant was randomly assigned 1:1 to a 670-nm light-emitting PBM eye patch or an identical device emitting broad-spectrum white light at low power. Treatment was applied for 90 seconds twice daily for 4 months. MAIN OUTCOME MEASURES: Change in CST on spectral-domain OCT at 4 months. RESULTS: From April 2019 to February 2020, 135 adults were randomly assigned to either PBM (n = 69) or placebo (n = 66); median age was 62 years, 37% were women, and 82% were White. The median device compliance was 92% with PBM and 95% with placebo. OCT CST increased from baseline to 4 months by a mean (SD) of 13 (53) µm in PBM eyes and 15 (57) µm in placebo eyes, with the mean difference (95% confidence interval [CI]) being -2 (-20 to 16) µm (P = 0.84). CI-DME, based on DRCR Retina Network sex- and machine-based thresholds, was present in 61 (90%) PBM eyes and 57 (86%) placebo eyes at 4 months (adjusted odds ratio [95% CI] = 1.30 (0.44-3.83); P = 0.63). VA decreased by a mean (SD) of -0.2 (5.5) letters and -0.6 (4.6) letters in the PBM and placebo groups, respectively (difference [95% CI] = 0.4 (-1.3 to 2.0) letters; P = 0.64). There were 8 adverse events possibly related to the PBM device and 2 adverse events possibly related to the placebo device. None were serious. CONCLUSIONS: PBM as given in this study, although safe and well-tolerated, was not found to be effective for the treatment of CI-DME in eyes with good vision.

Biologic Therapy and Treatment Options in Diabetic Retinopathy with Diabetic Macular Edema.

Proliferative diabetic retinopathy and diabetic macular edema can be a potentially sightthreatening disease if not treated correctly. It is directly correlated to the duration of diabetes and how well managed the patients' diabetes is. In the last 15 years, the treatment of diabetic eye disease has taken a quantum leap in methodology due to the group of biological agents named antivascular endothelial growth factor (anti-VEGF). The introduction of the first biological agent has revolutionized the treatment, not only in diabetic eye disease but also across most inflammatory eye diseases, causing leakage of fluid from the blood vessels i.e., in age-related macular degeneration. The availability of these biological agents, despite their considerable costs, have significantly improved the outcomes measured in visual acuity compared to more traditional treatments of diabetic retinopathy in the form of sole laser treatment and glycemic control. The agents demonstrate a favorable safety profile, but if the rarest and most severe side effects occur, there is a potential total loss of vision. This review aims to make an overview of the current pharmaceutical therapeutic options in the treatment of diabetic macular edema. This includes laser therapy, intravitreal steroids, and a primary focus on intravitreal antivascular endothelial growth factors.

Association between Serum Vitamin D and Diabetic Retinopathy in Portuguese Patients with Type 1 Diabetes.

INTRODUCTION: Recently, vitamin D has gained importance as a diabetes risk modifier. Our aim was to assess the association between serum vitamin D levels and the prevalence of diabetic retinopathy in patients with type 1 diabetes. MATERIAL AND METHODS: Retrospective review of a population of patients with type 1 diabetes followed in a Portuguese tertiary center. Patients were included if they had an ophthalmological evaluation and a serum 25-hydroxyvitamin D level determination within the same year. Logistic regression analysis was used to adjust for possible confounders. RESULTS: We included 182 patients (47% male), and 57% (n = 103) had signs of diabetic retinopathy. We found a significant association between lower circulating levels of 25-hydroxyvitamin D levels and a greater prevalence of diabetic retinopathy after adjusting for confounders (duration of diabetes, estimated glomerular filtration rate, age, sex, metabolic control, season, dyslipidemia and hypertension) (OR = 0.94; 95% CI 0.90 - 0.99, p = 0.023). Longer duration of diabetes and worse metabolic control also remained associated with diabetic retinopathy in the multivariate analysis (OR = 1.20; 95% CI 1.13 - 1.27, p < 0.001 and OR = 4.13; 95% CI 1.34 - 12.7, p = 0.013, respectively). CONCLUSION: Lower levels of vitamin D were associated with an increased prevalence of diabetic retinopathy in patients with type 1 diabetes, after adjusting for possible confounders. Future controlled studies may elucidate the molecular routes for this association as well as the role of supplementation in the prevention of diabetes microvascular complications.

Introdução: A vitamina D tem vindo a ganhar importância como um modificador do risco de diabetes. O objetivo deste estudo foi avaliar a associação entre os níveis séricos de vitamina D e a prevalência de retinopatia diabética em pacientes com diabetes tipo 1. Material e Métodos: Estudo retrospetivo de uma população de doentes com diabetes tipo 1, seguidos num centro hospitalar terciário português. Os pacientes foram incluídos se tivessem uma avaliação oftalmológica e um doseamento dos níveis de 25-hidroxivitamina D no mesmo ano. Os ajustes para eventuais variáveis confundidoras foi realizado recorrendo a uma análise de regressão logística. Resultados: Foram incluídos 182 doentes (47% sexo masculino), dos quais 57% (n = 103) demonstravam sinais de retinopatia diabética. Foi encontrada uma associação significativa entre níveis inferiores de 25-hidroxivitamina D circulante sérica e uma maior prevalência de retinopatia diabética, depois do ajuste para os confundidores incluídos (duração da diabetes, taxa de filtração glomerular estimada, idade, sexo, controlo metabólico, estação do ano, dislipidemia e hipertensão) (OR = 0,94; 95% IC 0,90 - 0,99, p = 0,023). Uma maior duração da diabetes, assim como um pior controlo metabólico, mantiveram também uma associação significativa com uma maior prevalência de retinopatia diabética na análise multivariada (OR = 1,20; 95% IC 1,13 - 1,27, p < 0,001; OR = 4,13; 95% IC 1,34 - 12,7, p = 0,013, respetivamente). Conclusão: Níveis inferiores de vitamina D séricos demonstraram-se associados a uma prevalência superior de retinopatia diabética em pacientes com diabetes tipo 1, após o ajuste para eventuais variáveis confundidoras. Futuramente, estudos experimentais poderão estabelecer as vias moleculares implicadas nesta associação, assim como um papel concreto da suplementação na prevenção das complicações microvasculares da diabetes.

The effects of hyperbaric oxygen therapy on diabetic retinopathy: A preliminary study.

PURPOSE: The objective of this study was to prospectively assess the effect of hyperbaric oxygen therapy (HBOT) on diabetic retinopathy lesions and macular edema in patients undergoing the treatment for diabetic foot ulcers. METHODS: We compared two groups: a first group including 25 patients with non-proliferative diabetic retinopathy treated by HBOT for foot ulcers, and a second group (control group) composed of 25 patients with diabetic retinopathy who did not receive HBOT. The HBOT protocol performed for the patients in the first group was: 30 sessions of 90 minutes each at 2.5 ATA with a mean frequency of five sessions per week. All patients had an ophthalmological exam at baseline (visual acuity, intraocular pressure, fundus exam), fundus photography and an OCT exam. A follow-up exam was performed at the conclusion of the HBOT. RESULTS: Compared to the control group, patients treated with HBOT showed a regression or stabilization of diabetic retinopathy lesions and a decrease in central macular thickness (CMT). CONCLUSION: Hyperbaric oxygen therapy may improve diabetic retinopathy and diabetic macular edema. This therapy may serve as an adjunctive treatment in the management of retinal ischemia and capillary hyperpermeability in diabetic retinopathy.

OMICs approaches-assisted identification of macrophages-derived MIP-1γ as the therapeutic target of botanical products TNTL in diabetic retinopathy.

BACKGROUND: Inflammatory reaction in the dysfunction of retinal endotheliocytes has been considered to play a vital role in diabetic retinopathy (DR). Anti-inflammatory therapy so far gains poor outcome as DR treatment. This study aims to identify a novel therapeutic target of DR from the OMICs studies of a traditional anti-DR botanical products TNTL. METHODS: Hyperglycemic mice were treated with TNTL. The anti-hyperglycemic effect of TNTL was validated to confirm the biological consistency of the herbal products from batches. Improvement of DR by TNTL was examined by various assays on the retina. Next-generation transcriptome sequencing and cytokine array was used to identify the therapeutic targets. In vitro study was performed to validate the target. RESULTS: We observed that TNTL at its high doses possessed anti-hyperglycemic effect in murine type I diabetic model, while at its doses without reducing blood glucose, it suppressed DR incidence. TNTL restored the blood-retina barrier integrity, suppressed retinal neovascularization, and attenuated the retinal ganglion cell degeneration. Transcriptomic analysis on the retina tissue of hyperglycemic mice with or without TNTL revealed that the inflammatory retina microenvironment was significantly repressed. TNTL treatment suppressed pro-inflammatory macrophages in the retina, which resulted in the inactivation of endothelial cell migration, restoration of endothelial cell monolayer integrity, and prevention of leakage. Cytokine array analysis suggested that TNTL could significantly inhibit the secretion of MIP1γ from pro-inflammatory macrophages. Prevention of endothelial dysfunction by TNTL may be mediated by the inhibition of MIP1γ/CCR1 axis. More specifically, TNTL suppressed MIP1γ release from pro-inflammatory macrophages, which in turn inhibited the activation of CCR1-associated signaling pathways in endothelial cells. CONCLUSION: Our findings demonstrated that TNTL might be an alternative treatment to DR, and the primary source of potential drug candidates against DR targeting MIP1γ/CCR1 axis in the retinal microenvironment.

TRActional DIabetic reTInal detachment surgery with co-adjuvant intravitreal dexamethasONe implant: the TRADITION STUDY.

AIM: Main failure of diabetic tractional retinal detachment (TRD) surgery is the development of proliferative vitreoretinopathy (PVR), causing higher re-detachment rates. We investigated whether the use of dexamethasone (DEX) implant at the end of pars plana vitrectomy (PPV) with silicone oil tamponade might have an impact on these outcomes. DESIGN: Comparative, nonrandomized, retrospective study. PARTICIPANTS: A total of 148 eyes from 148 patients that underwent PPV with silicone oil tamponade for diabetic TRD (with DEX implant, n = 52; without DEX implant, n = 96). METHODS: Consecutive patients' records were reviewed for time between TRD diagnosis and surgery; lens status before surgery and after 6, 12, and 24 months; retina attachment rate after primary PPV; change in postoperative PVR severity; rate of re-detachment at 6, 12, and 24 months; use of IOP lowering treatment after 6, 12, and 24 months; surgery details; intra- and postoperative complications. Correlations between outcome measures, postoperative PVR severity, and re-detachment rates were analyzed. MAIN OUTCOME MEASURES: Change in postoperative PVR severity and retinal re-detachment rates with and without the adjuvant use of DEX implant. RESULTS: Retinal re-detachment rates were significantly higher in the group of patients that did not receive DEX implant [11/96 (11.5%) vs. 0/52 (0%), p = 0.049; 11/84 (12.9%) vs. 4/52 (7.7%), p = 0.007; 14/71 (19.7%) vs. 5/52 (10%) p < 0.001 at 6, 12, and 24 months, respectively]. PVR severity correlated with retinal status at 12 and 24 months (p = 0.018 and p = 0.027, respectively). The difference in PVR severity between the two groups was statistically significant at 6, 12, and 24 months (p < 0.001). CONCLUSIONS: DEX implant at the end of PPV in patients with diabetic TRD improves PVR severity and decreases re-detachment rates. This should be considered as an option in the customized treatment of TRD.

Intravitreal fluocinolone acetonide implant (ILUVIEN®) for diabetic macular oedema: a literature review.

Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy and may lead to severe visual loss. In this review, we describe the pathophysiology of DMO and review current therapeutic options such as macular laser photocoagulation, anti-vascular endothelial growth factor agents, and steroid implants with a focus on the new fluocinolone acetonide implant, ILUVIEN®. The results of the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) studies are also presented together with the results of real-world studies to support the clinical use of ILUVIEN® in achieving efficient resolution of DMO and improving vision and macular anatomy in this challenging group of patients.

THREE-YEAR OUTCOMES IN A RANDOMIZED SINGLE-BLIND CONTROLLED TRIAL OF INTRAVITREAL RANIBIZUMAB AND ORAL SUPPLEMENTATION WITH DOCOSAHEXAENOIC ACID AND ANTIOXIDANTS FOR DIABETIC MACULAR EDEMA.

PURPOSE: To report 3-year results of a randomized single-blind controlled trial of intravitreal ranibizumab combined with oral docosahexaenoic acid (DHA) supplementation versus ranibizumab alone in patients with diabetic macular edema. METHODS: There were 26 patients (31 eyes) in the DHA group and 29 (38 eyes) in the control group. Ranibizumab (0.5 mg) was administered monthly for the first 4 months followed by a pro re nata (PRN) regimen. In the experimental group, patients received oral DHA supplementation (1,050 mg/day) (Brudyretina 1.5 g). RESULTS: At 36 months, mean decrease of central subfield macular thickness was higher in the DHA-supplementation group than in controls (275 ± 50 µm vs. 310 ± 97 µm) with significant differences at Months 25, 30, 33, and 34. Between-group differences in best-corrected visual acuity were not found, but the percentages of ETRDS gains >5 and >10 letters were higher in the DHA-supplementation group. Differences serum HbA1c, plasma total antioxidant capacity values, erythrocyte DHA content, and serum IL-6 levels were all significant in favor of the DHA-supplementation group. CONCLUSION: The addition of a high-rich DHA dietary supplement to intravitreal ranibizumab was effective to achieve better sustained improvement of central subfield macular thickness outcomes after 3 years of follow-up as compared with intravitreal ranibizumab alone.

Effects of ß-glucan and Vitamin D Supplementation on Inflammatory Parameters in Patients with Diabetic Retinopathy.

The objective of this article is to evaluate the potential effects of beta-glucan and vitamin D supplementation in patients with diabetic retinopathy. We evaluated the levels of several parameters of inflammatory reactions (C-reactive protein [CRP], serum amyloid A [SAA], and interleukin- [IL-] 6), leptin, and vitamin D. Using a 3-month interval, we divided the patients into three groups: (1) supplemented with beta-glucan and vitamin D, (2) supplemented with vitamin D and placebo, and (3) supplemented with vitamin D alone. By this division, we aim not only to observe whether beta-glucan can increase the effects of vitamin D, but also to eliminate the potential effects of placebo. The doses of vitamin D corresponded to phototype, weight, age, and sex of the individual. Fifty-two diabetic retinopathy patients were selected for our study. We found significant vitamin D deficits in all cases, even after three months of supplementation with vitamin D. Significant changes in levels of CRP were observed in the beta-glucan-supplemented group; levels of SAA and IL-6 were not changed. Leptin levels were significantly lowered in the beta-glucan-supplemented group and increased in the other groups. More detailed studies and/or longer supplementation is necessary.

Silymarin prevents diabetes-induced hyperpermeability in human retinal endothelial cells / La silimarina previene la hiperpermeabilidad inducida por la diabetes en células endoteliales de retina humana

Introduction: Vascular endothelial growth factor (VEGF) plays an essential role in development of diabetic macular edema (DME). While there is evidence suggesting that silymarin, a flavonoid extracted from Silybum marianum, could be useful for prevention and treatment of diabetic nephropathy, no studies have been conducted in diabetic retinopathy (DR). The aim of this study was to assess the effect of silymarin on disruption of inner blood retinal barrier (BRB), the primary cause of DME. Materials and methods: Human retinal endothelial cells (HRECs) were cultured under standard (5.5mM D-glucose) and diabetogenic conditions (25mM D-glucose and 25mM D-glucose + recombinant vascular endothelial growth factor [rVEGF, 25mg/mL]). To assess cell viability, three concentrations of silymarin were tested (2, 4 and 10μg/mL). The effect of silymarin on HREC disruption was determined using a dextran (70kD) permeability asssay. Results: No differences were found in the viability of HRECs treated with 2 or 4μg/mL of silymarin as compared to untreated cells, but viability significantly decreased after using 10 μg/mL. The concentration of 4 μg/mL was therefore selected. Silymarin (4μg/mL) caused a significant decrease in VEGF-induced permeability in both media with 5.5nM (422±58 vs. 600±72 ng/mL/cm2; p<0.03) and 25nM of D-glucose (354 ± 28 vs. 567 ± 102 ng/mL/cm2; p<0.04). Discussion: Our results show that silymarin is effective for preventing hyperpermeability induced by diabetic conditions in HRECs. Further studies are needed to assess whether silymarin could be useful to treat DME (AU)

Introducción: El Vascular endothelial growth factor (VEGF) juega un papel esencial en el desarrollo del edema macular diabético (EMD). Existe evidencia que indica que el uso de la silimarina, extracto flavonoide del Silybum marianum, podría ser útil en la prevención y el tratamiento de la nefropatía diabética pero no se dispone de datos en retinopatía diabética (RD). El objetivo del estudio es evaluar el efecto de la silimarina sobre la disrupción de la barrera hematorretininana, que es la causa primaria del EMD. Material y métodos: Células endoteliales de retina humana (HRECs) se cultivaron en condiciones estándar (5.5mM de D-glucosa) y en condiciones suprafisiológicas de glucosa (25mM de D-glucosa y 25mM de D-glucosa + VEGF 25mg/dl). Para evaluar la viabilidad de las células se probaron 3 concentraciones de silimarina (2, 4 y 10μg/ml). El efecto de la silimarina sobre la disrupción de las HRECs se determinó mediante análisis de permeabilidad a dextrano (70kD). Resultados: No se observaron diferencias en la viabilidad de las HRECs tratadas con 2 o 4μg/ml de silimarina en comparación con las células no tratadas, pero se observó una reducción de la viabilidad con la concentración de 10μg/ml. Por consiguiente, se seleccionó la concentración de 4μg/ml de silimarina. La silimarina (4μg/ml) produjo un descenso significativo de la permeabilidad inducida por VEGF tanto en medio con 5.5mM de D-glucosa (422 ±58 vs. 600 ±72 ng/ml/cm2; p<0.03) como en medio con 25mM de D-glucosa (354±28 vs. 567±102 ng/ml/cm2; p<0.04). Discusión: Nuestros resultados demuestran que la silimarina es efectiva para prevenir la hiperpermeabilidad inducida por condiciones suprafisiológicas de glucosa en HRECs. Son necesarios más estudios para evaluar si la silimarina podría ser útil para el tratamiento del EMD (AU)