Sobha Sivaprasad

Circulating MicroRNAs as Novel Biomarkers for Platelet Activation

Rationale: MicroRNA (miRNA) biomarkers are attracting considerable interest. Effects of medication, however, have not been investigated thus far. Objective: To analyze changes in plasma miRNAs in response to antiplatelet therapy. Methods and Results: Profiling for 377 miRNAs was performed in platelets, platelet microparticles, platelet-rich plasma, platelet-poor plasma, and serum. Platelet-rich plasma showed markedly higher levels of miRNAs than serum and platelet-poor plasma. Few abundant platelet miRNAs, such as miR-24, miR-197, miR-191, and miR-223, were also increased in serum compared with platelet-poor plasma. In contrast, antiplatelet therapy significantly reduced miRNA levels. Using custom-made quantitative real-time polymerase chain reaction plates, 92 miRNAs were assessed in a dose-escalation study in healthy volunteers at 4 different time points: at baseline without therapy, at 1 week with 10 mg prasugrel, at 2 weeks with 10 mg prasugrel plus 75 mg aspirin, and at 3 weeks with 10 mg prasugrel plus 300 mg aspirin. Findings in healthy volunteers were confirmed by individual TaqMan quantitative real-time polymerase chain reaction assays (n=9). Validation was performed in an independent cohort of patients with symptomatic atherosclerosis (n=33), who received low-dose aspirin at baseline. Plasma levels of platelet miRNAs, such as miR-223, miR-191, and others, that is, miR-126 and miR-150, decreased on further platelet inhibition. Conclusions: Our study demonstrated a substantial platelet contribution to the circulating miRNA pool and identified miRNAs responsive to antiplatelet therapy. It also highlights that antiplatelet therapy and preparation of blood samples could be confounding factors in case-control studies relating plasma miRNAs to cardiovascular disease.

Prevalence of Diabetic Retinopathy in Various Ethnic Groups: A Worldwide Perspective

The alarming rise in diabetes prevalence is a global public health and economic problem. Diabetic retinopathy is the most common complication of diabetes and the leading cause of blindness among working-age populations in the Western world. Screening and prompt treatment of diabetic retinopathy are not top priorities in many regions of the world, because the impacts of other causes of preventable blindness remain an issue. Ethnicity is a complex, independent risk factor for diabetic retinopathy. Observations from white populations cannot be extrapolated fully to other ethnic groups. The prevalence of diabetic retinopathy, sight-threatening diabetic retinopathy, and clinically significant macular edema are higher in people of South Asian, African, Latin American, and indigenous tribal descent compared to the white population. Although all ethnic groups are susceptible to the established risk factors of diabetic retinopathy-such as length of exposure and severity of hyperglycemia, hypertension, and hyperlipidemia-ethnic-specific risk factors also may influence these rates. Such risk factors may include differential susceptibility to conventional risk factors, insulin resistance, differences in anthropometric measurements, truncal obesity, urbanization, variations in access to healthcare systems, genetic susceptibility, and epigenetics. The rates of nonproliferative diabetic retinopathy appear to be declining in the United States, supporting the observation that better medical management of diabetes and prompt treatment of sight-threatening diabetic retinopathy substantially improve the long-term diabetic retinopathy incidence; studies from other parts of the world are limited and do not mirror this finding, however. We examine the ethnicity and region-based prevalence of diabetic retinopathy around the world and highlight the need to reinforce ethnicity-based screening and treatment thresholds in diabetic retinopathy.

Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration

Background/aims Real-life anti-vascular endothelial growth factor (VEGF) therapy use in patients with wet age-related macular degeneration (wAMD) was assessed in a retrospective, observational study in Canada, France, Germany, Ireland, Italy, the Netherlands, UK and Venezuela. Methods Medical records of patients with wAMD, who started ranibizumab treatment between 1 January 2009 and 31 August 2009, were evaluated. Data were collected until the end of treatment and/or monitoring or until 31 August 2011. Results 2227 patients who received ≥1 anti-VEGF injection with a baseline visual acuity assessment and ≥1 postbaseline visual acuity assessment for the treated eye were evaluated. Visual acuity improved until about day 120; thereafter, visual acuity gains were not maintained. Mean change in visual acuity score from baseline to years 1 and 2 was +2.4 and +0.6 letters, respectively. Patients received a mean of 5.0 and 2.2 injections in the first and second year, respectively. There were substantial differences in visual outcomes and injection frequency between countries. More frequent visits and injections were associated with greater improvements in visual acuity. Conclusions In clinical practice, fewer injections are administered than in clinical trials. Anti-VEGF treatment resulted in an initial improvement in visual acuity; however, this was not maintained over time. Trial registration number NCT01447043.

Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema

Aim: The study was a prospective randomised controlled double-masked trial performed in two centres to compare sub-threshold micropulse diode laser photocoagulation (MPDL) with conventional green laser photocoagulation (CGL) in the treatment of clinically significant diabetic macular oedema (CSMO). Methods: Fifty-three patients (84 eyes) with diabetic CSMO were randomly assigned to MPDL (n = 44) or CGL (n = 40) according to the modified Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Treatments were performed after baseline and re-treatments were allowed at or after the 4 month visit if necessary. Parameters noted included the best corrected visual acuity (BCVA), colour fundus photographs, central retinal thickness using optical coherence tomography (OCT), vision contrast sensitivity with Pelli–Robson charts and presence of visible laser scars at baseline and at 4 and 12 months. The primary outcome was BCVA at 12 months. Results: All patients completed 12 months of follow-up after treatment at baseline. There were no statistically significant differences in BCVA, contrast sensitivity and retinal thickness between the two laser modalities at 0, 4 and 12 months. We found that laser scarring was much more apparent with CGL than with the sub-threshold approach (MPDL). Laser scars were identified at the 12 month visits in 13.9% of the MPDL-treated eyes compared with 59.0% of the CGL-treated eyes (p<0.001). Conclusion: Sub-threshold micropulse diode laser photocoagulation is equally as effective as CGL treatment for CSMO. Trial registration number: ISTRN 90646644.

Treatment of proliferative diabetic retinopathy with anti-VEGF agents.

Proliferative diabetic retinopathy (PDR) is the most common cause of severe visual loss in people with diabetes. Although panretinal photocoagulation (PRP) remains the gold standard of care to date, several combinations of new treatment modalities have emerged. These approaches can be used to increase the extent of treatment, expedite the effect of laser treatment and provide alternate measures when laser delivery is difficult or impossible, especially in patients with vitreous haemorrhage. Currently, most of the research in this field is focussed on inhibitors of vascular endothelial growth factor (VEGF), referred to herein as anti‐VEGF agents. Although limited by their short‐lived effects and a lack of established protocols, anti‐VEGF agents are widely available, especially for the treatment of aggressive PDR. This review analyses published studies using anti‐VEGF agents alone or as an adjunct to other therapies in the treatment of PDR.

Micropulsed Diode Laser Therapy: Evolution and Clinical Applications

Many clinical trials have demonstrated the clinical efficacy of laser photocoagulation in the treatment of retinal vascular diseases, including diabetic retinopathy. There is, however, collateral iatrogenic retinal damage and functional loss after conventional laser treatment. Such side effects may occur even when the treatment is appropriately performed because of morphological damage caused by the visible endpoint, typically a whitening burn. The development of the diode laser with micropulsed emission has allowed subthreshold therapy without a visible burn endpoint. This greatly reduces the risk of structural and functional retinal damage, while retaining the therapeutic efficacy of conventional laser treatment. Studies using subthreshold micropulse laser protocols have reported successful outcomes for diabetic macular edema, central serous chorioretinopathy, macular edema secondary to retinal vein occlusion, and primary open angle glaucoma. The report includes the rationale and basic principles underlying micropulse diode laser therapy, together with a review of its current clinical applications.

Sickle cell disease and the eye: old and new concepts.

The pathophysiology of sickle cell disease is not limited to abnormal red blood cells. The clinical manifestations of sickle cell disease include complex pathways and processes such as endothelial activation, inflammation, bioavailability of nitric oxide, oxidative stress, and the adhesiveness of a variety of blood cells. Increasingly, distinct subphenotypes and genetic modifiers of sickle cell disease are being recognized. We apply recent advances in sickle cell disease to ocular biology to highlight translational research in this field and encourage additional studies on the ocular manifestations of sickle cell disease.

Ethnic Variations in the Prevalence of Diabetic Retinopathy in People with Diabetes Attending Screening in the United Kingdom (DRIVE UK)

Aims To compare the prevalence of diabetic retinopathy (DR) in people of various ethnic groups with diabetes in the United Kingdom (UK). Methods The Diabetic Retinopathy In Various Ethnic groups in UK (DRIVE UK) Study is a cross-sectional study on the ethnic variations of the prevalence of DR and visual impairment in two multi-racial cohorts in the UK. People on the diabetes register in West Yorkshire and South East London who were screened, treated or monitored between April 2008 to July 2009 (London) or August 2009 (West Yorkshire) were included in the study. Data included age, sex, ethnic group, type of diabetes, presenting visual acuity and the results of grading of diabetic retinopathy. Prevalence estimates for the ethnic groups were age-standardised to the white European population for comparison purposes. Results Out of 57,144 people on the two diabetic registers, data were available on 50,285 individuals (88.0%), of these 3,323 had type 1 and 46,962 had type 2 diabetes. In type 2 diabetes, the prevalence of any DR was 38.0% (95% confidence interval(CI) 37.4% to 38.5%) in white Europeans compared to 52.4% (51.2% to 53.6%) in African/Afro-Caribbeans and 42.3% (40.3% to 44.2%) in South Asians. Similarly, sight threatening DR was also significantly more prevalent in Afro-Caribbeans (11.5%, 95% CI 10.7% to 12.3%) and South Asians (10.3%, 9.0% to 11.5%) compared to white Europeans (5.5%, 5.3% to 5.8%). Differences observed in Type 1 diabetes did not achieve conventional levels of statistical significance, but there were lower numbers for these analyses. Conclusions Minority ethnic communities with type 2 diabetes in the UK are more prone to diabetic retinopathy, including sight-threatening retinopathy and maculopathy compared to white Europeans.

Loss of chromatic sensitivity in AMD and diabetes: a comparative study.

Background:  Abnormalities in rod and cone photoreceptor morphology have been reported in normal aging retinas in the absence of known pathology and have been taken as an indicator of susceptibility to retinal disease. Some loss of visual performance may therefore precede retinal structural changes that can be detected reliably using conventional fundus imaging techniques. Red/green (RG) and yellow/blue (YB) colour discrimination thresholds are sensitive measures of normal retinal function and poor YB discrimination is often taken as an indicator of retinal disease, though it is generally acknowledged that RG loss is also present in most cases of acquired deficiency. Although structural changes in age‐related macular degeneration (AMD) and diabetes share some similarities, significant differences remain and this may result in different patterns of RG and YB loss.

Socio-economic and ethnic inequalities in diabetes retinal screening.

Diabet. Med. 27, 282–288 (2010)