Mechanistic Insights into Immunological Therapy for Targeting Diabetic Retinopathy

Diabetic retinopathy (DR) is a common complication amongst patients that have diabetes. It is a leading cause of blindness in middle age people. A large proportion of patients who have diabetes develop retinopathy. There are several immunological reasons associated with the pathophysiology of this disease. Role of several mediators that increase the oxidative stress and have a pro-inflammatory effect which leads to capillary occlusion and neovascularization (NV). Increased vasopermeability due to disruption of the blood-retinal barrier (BRB) leading to diabetic macular edema (DME). Immunotherapies utilise different compounds and target various inflammatory molecules like TNF-α and pathways such as PPARγ for treatment of this progressive disease. Inflammatory and pro-inflammatory pathways are found to have an essential role in promoting DR; therefore, targeting them provides a useful technique for curing DR.

Mechanistic Insights into Immunological Therapy for Targeting Diabetic Retinopathy

Diabetic retinopathy (DR) is a common complication amongst patients that have diabetes. It is a leading cause of blindness in middle age people. A large proportion of patients who have diabetes develop retinopathy. There are several immunological reasons associated with the pathophysiology of this disease. Role of several mediators that increase the oxidative stress and have a pro-inflammatory effect which leads to capillary occlusion and neovascularization (NV). Increased vasopermeability due to disruption of the blood-retinal barrier (BRB) leading to diabetic macular edema (DME). Immunotherapies utilise different compounds and target various inflammatory molecules like TNF-α and pathways such as PPARγ for treatment of this progressive disease. Inflammatory and pro-inflammatory pathways are found to have an essential role in promoting DR; therefore, targeting them provides a useful technique for curing DR.

Retinal ultra-wide-field colour imaging versus dilated fundus examination to screen for sickle cell retinopathy

PurposeTo compare ultra-wide-field colour fundus imaging (UWFI) to dilated fundus examination (DFE) for the screening of sickle cell retinopathy (SCR).DesignThis study is a prospective, blinded, multicentre case series.ParticipantsThis study included two groups: an adult group (n=268 eyes) and a paediatric group (n=168 eyes). Sickle cell disease (SCD) types included haemoglobin S homozygous (HbSS), haemoglobin S and C (HbSC) and Hb S with β-thalassaemia (HbSß-Thal).MethodsParticipants underwent DFE and UWFI. Each eye received three independent grades (1–4), documented by three graders: clinical grader, image grader 1 and image grader 2. Three clinically relevant diagnostic thresholds were determined. Based on these thresholds, the sensitivity, specificity, positive predictive value and negative predictive value for all three graders were calculated relative to each other as reference tests.ResultsHbSC was associated with the most advanced SCR grades. When compared to the clinical grader, image grader 1 and image grader 2 consistently detected more SCR and higher SCR grades in both adult and paediatric groups. In both groups, image grader 1 and image grader 2 identified twice as many cases of capillary occlusion/anastomosis than clinical grader. To detect the presence of any proliferative SCR, image grader 1 and image grader 2 had a sensitivity of 82%, 71% in the paediatrics group and 90% and 72% in the adult group. The clinical grader sensitivity was 52% in the paediatrics group and 53% in the adult group.ConclusionThe UWFI is a sensitive tool to screen for SCR. It is superior to DFE in detecting capillary occlusion or anastomosis.

Morphophysiological characteristics of skin microcirculation types in patients with Dupuytren’s contracture

Aim– to investigate the patterns of cutaneous microcirculation and their relationship with structural vascular changes in palmar hypoderm in patients with Dupuytren’s disease.Material and methods. In 26 patients with Dupuytren’s contracture aged between 45 and 70 years, the microcirculation of palmar skin was assessed before the planned surgical treatment using ultrasound pulsed Doppler (Minimax-Doppler K, SP Minimax, St. Petersburg, Russia) with a high-frequency sensor of 20 MHz and laser Doppler flowmetry (BLF21, Transonic Systems Inc., USA). The local 3-minute arterial ischemic test was performed in all patients by putting the occlusion cuff on the forearm. Histological analysis of intra-operative tissue specimens was done using light microscopy (Carl Zeiss Primo Star microscope with 3.1 MP UCMOS video camera) MicroCapture Ver 6.6 program was used for data acquisition.Results. The normocirculatory type of hemodynamics (1) was found in 17 % of observations; hyperemic (2) – in 19 %, congestive-spastic (3) – in 42 %, and congestive-static (4) – in 21 %. Histologically type 1 was characterized with initial signs of constrictive arterial remodeling and capillary occlusion, 2 – with marked hyperemia of the microcirculatory bed and diapedesis of blood cells, inflammatory perivascular infiltrates, 3 – with significant narrowing and deformations of lumens in small arteries and hyalinosis of arterioles, 4 – with pronounced polymorphism of capillary loops, significant changes in arteries and veins.Discussion. Hyperemic type of microcirculation reflects high activity of autoimmune inflammation. Congestic-spastic type indicates a significant decrease in the reactivity of precapillary microvessels. Congestic-stasic type is accompanied by the most pronounced constrictive vascular remodeling and denervation of the vascular bed.Conclusion. Dupuytren’s contracture is characterized with predominance of pathological types of microcirculation in palmar skin, which must be taken into account in individualized protocols of additive therapy.

A Computational Model of Peripheral Photocoagulation for the Prevention of Progressive Diabetic Capillary Occlusion

We developed a computational model of the propagation of retinal ischemia in diabetic retinopathy and analyzed the consequences of various patterns and sizes of burns in peripheral retinal photocoagulation. The model addresses retinal ischemia as a phenomenon of adverse local feedback in which once a capillary is occluded there is an elevated probability of occlusion of adjacent capillaries resulting in enlarging areas of retinal ischemia as is commonly seen clinically. Retinal burns of different sizes and patterns, treated as local oxygen sources, are predicted to have different effects on the propagation of retinal ischemia. The patterns of retinal burns are optimized with regard to minimization of the sum of the photocoagulated retina and computer predicted ischemic retina. Our simulations show that certain patterns of retinal burns are effective at preventing the spatial spread of ischemia by creating oxygenated boundaries across which the ischemia does not propagate. This model makes no statement about current PRP treatment of avascular peripheral retina and notes that the usual spot sizes used in PRP will not prevent ischemic propagation in still vascularized retinal areas. The model seems to show that a properly patterned laser treatment of still vascularized peripheral retina may be able to prevent or at least constrain the propagation of diabetic retinal ischemia in those retinal areas with intact capillaries.

Proregenerative Microenvironment Triggered by Donor Mesenchymal Stem Cells Preserves Renal Function and Structure in Mice with Severe Diabetes Mellitus

The aim of our work was to evaluate, in an animal model of severe diabetes mellitus, the effect of mesenchymal stem cells (MSCs) administration on diabetic nephropathy (DN) progression. After diabetes induction, one group of mice received the vehicle (DM) and other group received a single dose of MSCs (DM + MSCs). DM + MSCs mice showed a significant improvement in functional parameters of the kidney compared with untreated mice. While DM mice presented marked histopathological changes characteristics of advanced stages of DN (fibrosis, glomerulosclerosis, glomerular basement membrane thickening, capillary occlusion, decreased podocyte density, and effacement of foot processes), DM + MSCs mice showed only slight tubular dilatation. The renoprotection was not associated with an improvement in diabetic condition and very low number of donor cells was found in the kidney of DM + MSCs mice, suggesting that renoprotection could be mediated by paracrine effects. Indeed, DM + MSC mice presented increased renal proliferation index, decreased renal apoptotic index and the restoration of proregenerative factors, and anti-inflammatory cytokines levels. Moreover, macrophage infiltration and oxidative stress damage were also reduced in DM + MSCs mice. Our data demonstrate that MSC administration triggers a proregenerative microenvironment in DN kidney, which allows the preservation of the renal function even if diabetes was uncorrected.

Retinal arterial plaques in acquired immunodeficiency syndrome

The authors report the unusual observation discrete plaque like excrescencies along the retinal arterial wall in a young patient with acquired immunodeficiency syndrome. Though bilateral, in the right eye there was severe arteriolar narrowing and so these plaques were less identifiable. Fluorescein angiography did not reveal any arteriolar occlusion or areas of capillary occlusion in both eyes. There were no other signs of HIV associated microangiopathy and the patient did not have any concurrent cardiovascular or hematological abnormality. The cause of these plaques remains unexplained and we conjecture that they could represent <em>macro</em> immunecomplex deposition along the arteriolar walls.

Diabetic retinopathy: treatment and prevention

Diabetic eye disease is the major cause of blindness and vision loss among working-age people in developed countries. Microangiopathy and capillary occlusion underlie the pathogenesis of disease. While laser treatment is regarded as the standard therapy, intensive medical management of glycaemia and hypertension is also a priority in order to reduce the risk of diabetic retinopathy. Recent data have prompted a re-evaluation of the role of lipid-modifying therapy in reducing diabetic retinopathy. The Fenofibrate Intervention for Event Lowering in Diabetes (FIELD) study demonstrated a significant 30% relative reduction in the need for first retinal laser therapy in patients with (predominantly early-stage) type 2 diabetes treated with fenofibrate 200 mg daily, from 5.2% with placebo to 3.6% with fenofibrate, p=0.0003. The benefit of fenofibrate was evident within the first year of treatment. These promising data justify further evaluation of the mechanism and role of fenofibrate, in addition to standard therapy, in the management of diabetic retinopathy.