Natural history of retinopathy in children and young people with type 1 diabetes.

PurposeTo describe the prevalence and natural history of retinopathy in a cohort of children and young people with type 1 diabetes attending a tertiary hospital diabetes clinic.MethodsWe analysed retinopathy screening data from 2008 to 2010 on all eligible children using the 'Twinkle' diabetes database and the regional retinal screening database.ResultsA total of 88% (149/169) of eligible children were screened in 2008, median age 14 years, 52% male. The prevalence of retinopathy was 19.5% (30/149). All children had background retinopathy grade R1. There was significant difference in median (range) duration of diabetes, 7.7 years (0.6-13.7) vs 5 years (0.2-12.5) (P<0.001) and median (range) HbA1C, 9.1% (7.2-14) vs 8.6% (5.6-13.1) (P=0.02), between the groups with and without retinopathy. At 2- years follow-up, 12/30 (40%) had unchanged retinopathy grade R1, 10/30 (33.3%) showed resolution of changes (R0), 1/30 progressed to maculopathy, and 7/30 had no follow-up data. Median (range) HbA1C in 2008 and 2010 for the groups with stable vs resolved changes was similar, 9.1% (7.2-14.0) and 9.2% (7-14.0) vs 9.5% (7.8-14.0) and 9.2% (8.7-14.0). Of the 119 without retinopathy in 2008, 27 (22.5%) had developed retinopathy within 2 years, including 1 with pre-proliferative retinopathy and 1 with maculopathy. There was no significant difference in HbA1c between those who progressed to retinopathy (8.7% (7.1-13.1)) (8.7% (7.1-13.1)), and those who did not (8.6% (6.3-12.2)).ConclusionsPrevalence of background retinopathy in our cohort was comparable to the previously published reports, with higher HbA1c and longer duration of diabetes being significant risk factors. On short-term follow-up, Grade 1 retinopathy is likely to resolve in a third of patients and remain unchanged in just over a third.

Diagnosis of retinopathy in children younger than 12 years of age: implications for the diabetic eye screening guidelines in the UK.

AimTo assess whether the current starting age of 12 is suitable for diabetic retinopathy (DR) screening and whether diabetes duration should be taken into account when deciding at what age to start screening patients.Materials and methodsA retrospective analysis of 143 patients aged 12 years or younger who attended diabetic eye screening for the first time in the Birmingham, Solihull and Black Country Diabetic Eye Screening Programme was performed.ResultsThe mean age of the patients was 10.7 (7-12) years with 73 out of 143 aged below 12 years and 70 were 12 years of age. 98% had type 1 diabetes and mean diabetes duration was 5 (1 month-11 years) years. For those younger than 12 years, 7/73 (9.6%) had background DR (BDR), of these mean diabetes duration was 7 years (6-8). The youngest patient to present with DR was aged 8 years. In those aged 12 years, 5/70 (7.1%) had BDR; of these mean diabetes duration was 8 years (6-11). No patient developed DR before 6 years duration in either group.ConclusionsThe results show that no patient younger than the age of 12 had sight-threatening DR (STDR), but BDR was identified. Based on the current mission statement of the Diabetic Eye Screening Programme to identify STDR, 12 years of age is confirmed as the right age to start screening, but if it is important to diabetic management to identify first development of DR, then screening should begin after 6 years of diabetes diagnosis.

An Injured Psittacosaurus (Dinosauria: Ceratopsia) From the Yixian Formation (Liaoning, China): Implications for Psittacosaurus Biology.

We describe a Psittacosaurus specimen from the Lujiatun beds of the Yixian Formation in Liaoning, China with an abnormality on its left fibula. Although a large number of Psittacosaurus specimens are known, only a single example of a pathologic Psittacosaurus has been previously noted. The specific pathology in the current specimen is believed to be a healed fibular fracture as assessed through a combination of gross morphology, microcomputed tomography (microCT), and histology data. The fracture can be identified using microCT, but the degree of remodeling and the stage of fracture repair are best determined histologically. The fracture callus is made up of radially oriented spokes of woven bone in a cartilage matrix and the original cortical bone prior to the fracture has been largely eroded. A transverse histologic section taken at the level of the fracture shows the displacement of the proximal and distal parts of the fibula. The Psittacosaurus appears to have survived the break considering the deposition of circumferential non-pathologic bone at the periosteal surface outside of the callus. The combination of gross morphological description, microCT data, and histologic data allowed for a full diagnosis of the abnormality. While some previous authors have preferred gross morphological description above other methods for assessing paleopathologies, it is evident based on this specimen that an amalgam of techniques provides greater clarity to paleopathology diagnoses. Although this Psittacosaurus lived in an environment with many predators, it was able to survive with a fracture on its hindlimb, which undoubtedly would have impacted its locomotion. Anat Rec, 299:897-906, 2016. © 2016 Wiley Periodicals, Inc.

Evaluating digital diabetic retinopathy screening in people aged 90 years and over.

PURPOSE: To evaluate the effectiveness of digital diabetic retinopathy screening in patients aged 90 years and over. METHODS: This is a retrospective analysis of 200 randomly selected patients eligible for diabetic retinopathy screening aged 90 years and over within the Birmingham, Solihull, and Black Country Screening Programme. RESULTS: One hundred and seventy-nine (90%) patients attended screening at least once. OUTCOMES: 133 (74%) annual screening after their first screen, of whom 59% had no detectable diabetic retinopathy; 38 (21%) were referred for ophthalmology clinical assessment-36 for nondiabetic retinopathy reasons and two for diabetic maculopathy. Cataract accounted for 50% of all referrals for ophthalmology clinical assessment. Of the 133 patients placed on annual screening, 93 (70%) were screened at least once more. In terms of level of diabetic retinopathy, assessability or other ocular pathologies, 8 improved, 51 remained stable, and 31 deteriorated. Of the latter, 19 patients were referred for ophthalmology clinical assessment; none of these for diabetic retinopathy. CONCLUSIONS: Screening provides opportunistic identification of important nondiabetic retinopathy eye conditions. However, in view of the low identification rate of sight-threatening diabetic retinopathy in patients aged 90 years and over, and the current mission statement of the NHS Diabetic Eye Screening Programme, systematic annual diabetic retinopathy screening may not be justified in this age group of patients, but rather be performed in optometric practice.

Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema: a prospective, multicentre, UK study.

OBJECTIVES: To determine the best photographic surrogate markers for detecting sight-threatening macular oedema (MO) in people with diabetes attending UK national screening programmes. DESIGN: A multicentre, prospective, observational cohort study of 3170 patients with photographic signs of diabetic retinopathy visible within the macular region [exudates within two disc diameters, microaneurysms/dot haemorrhages (M/DHs) and blot haemorrhages (BHs)] who were recruited from seven study centres. SETTING: All patients were recruited and imaged at one of seven study centres in Aberdeen, Birmingham, Dundee, Dunfermline, Edinburgh, Liverpool and Oxford. PARTICIPANTS: Subjects with features of diabetic retinopathy visible within the macular region attending one of seven diabetic retinal screening programmes. INTERVENTIONS: Alternative referral criteria for suspected MO based on photographic surrogate markers; an optical coherence tomographic examination in addition to the standard digital retinal photograph. MAIN OUTCOME MEASURES: (1) To determine the best method to detect sight-threatening MO in people with diabetes using photographic surrogate markers. (2) Sensitivity and specificity estimates to assess the costs and consequences of using alternative strategies. (3) Modelled long-term costs and quality-adjusted life-years (QALYs). RESULTS: Prevalence of MO was strongly related to the presence of lesions and was roughly five times higher in subjects with exudates or BHs or more than two M/DHs within one disc diameter. Having worse visual acuity was associated with about a fivefold higher prevalence of MO. Current manual screening grading schemes that ignore visual acuity or the presence of M/DHs could be improved by taking these into account. Health service costs increase substantially with more sensitive/less specific strategies. A fully automated strategy, using the automated detection of patterns of photographic surrogate markers, is superior to all current manual grading schemes for detecting MO in people with diabetes. The addition of optical coherence tomography (OCT) to each strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. CONCLUSIONS: Compared with all current manual grading schemes, for the same sensitivity, a fully automated strategy, using the automated detection of patterns of photographic surrogate markers, achieves a higher specificity for detecting MO in people with diabetes, especially if visual acuity is included in the automated strategy. Overall, costs to the health service are likely to increase if more sensitive referral strategies are adopted over more specific screening strategies for MO, for only very small gains in QALYs. The addition of OCT to each screening strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. STUDY REGISTRATION: This study has been registered as REC/IRAS 07/S0801/107, UKCRN ID 9063 and NIHR HTA 06/402/49. SOURCE OF FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 51. See the HTA programme website for further project information.

Screening for diabetic retinopathy in pregnancy using photographic review clinics.

AIMS: To assess the efficacy and value of the National Institute for Health and Clinical Excellence guidelines for digital photographic screening for diabetic retinopathy in pregnancy using photographic review clinics. METHODS: Pregnant patients (n = 186) with known diabetes were screened at first antenatal visit and at 28 weeks' gestation, if no retinopathy was noted at first visit, or at other intervals if retinopathy was present. Two 45° images (disc-centred and macula-centred views) were taken in both eyes and graded by trained graders and by an ophthalmologist. RESULTS: Ninety-three patients (50%) remained free of diabetic retinopathy throughout pregnancy. Eighteen (10%) presented with sight-threatening retinopathy at their first antenatal screen and were referred to the hospital eye service. Fifty patients (27%) were shown to have relatively stable retinopathy throughout pregnancy, with only two patients deteriorating and requiring referral to hospital eye service. Twenty-three (12%) failed to complete the screening protocol after their first screen. CONCLUSIONS: The study showed that pregnant patients screened for retinopathy in an ophthalmic photographic diabetic review clinic achieved National Institute for Health and Clinical Excellence guidelines in the majority and were clinically safe. Only 1% of patients required referral to ophthalmology after their initial screen, thus avoiding unnecessary hospital eye service appointments.

Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) display features of overlap in airway physiology and airway inflammation. Whether inflammatory phenotypes in airway disease describe similar mediator expression is unknown. OBJECTIVES: To explore the relationship of airway inflammation and cytokine and chemokine expression in asthma and COPD. METHODS: Subjects with asthma and COPD (n = 54 and n = 49) were studied. Clinical characteristics and sputum were collected at entry into the study. A 2-step sputum processing method was performed for supernatant and cytospin preparation. Meso Scale Discovery and Luminex platforms were used to measure cytokines, chemokines and matrix metalloproteinase levels. RESULTS: Analytes sensitive to dithiothreitol (DTT) that had increased recovery in the 2-step sputum process were IL-1ß, 4, 5, 10, 13, IFN-γ, TNFRI, GM-CSF, CCL2, 3, 4, 5, 13 and 17. There was a differential expression in IL-8, TNFRI and TNFRII between asthma and COPD [mean fold difference (95% CI): IL-8, 2.6 (1.3-5.4), p = 0.01; TNFRI, 2.1 (1.3-5.4), p = 0.03; TNFRII, 2.6 (1.2-5.6), p = 0.02]. In neutrophilic and eosinophilic airway inflammation, TNFα, TNFRI, TNFRII, IL-6, IL-8 and IL-5 could differentiate between these phenotypes. However, these phenotypes were unrelated to the diagnosis of asthma or COPD. CONCLUSION: Recovery of sputum mediators sensitive to DTT can be improved using the described sputum processing technique. Within airway inflammatory sub-phenotypes there is a differential pattern of mediator expression that is independent of disease. Whether these inflammatory phenotypes in asthma and COPD confer distinct pathogeneses, therapeutic responses and clinical phenotypes needs to be further evaluated.

Trace metals as biomarkers for eumelanin pigment in the fossil record.

Well-preserved fossils of pivotal early bird and nonavian theropod species have provided unequivocal evidence for feathers and/or downlike integuments. Recent studies have reconstructed color on the basis of melanosome structure; however, the chemistry of these proposed melanosomes has remained unknown. We applied synchrotron x-ray techniques to several fossil and extant organisms, including Confuciusornis sanctus, in order to map and characterize possible chemical residues of melanin pigments. Results show that trace metals, such as copper, are present in fossils as organometallic compounds most likely derived from original eumelanin. The distribution of these compounds provides a long-lived biomarker of melanin presence and density within a range of fossilized organisms. Metal zoning patterns may be preserved long after melanosome structures have been destroyed.

Does microvascular disease predict macrovascular events in type 2 diabetes?

AIM: Population studies suggest a link between albuminuria, reduced glomerular filtration rate (GFR) and retinopathy and macrovascular events in type 2 diabetes. The aim of this review was to investigate whether this association extended to the presence of any diabetic microvascular complication. METHOD AND RESULTS: PUBMED was searched from 1999 to 2010 using the terms 'albuminuria', 'nephropathy', 'chronic kidney disease', 'estimated GFR', 'retinopathy', 'autonomic neuropathy', 'peripheral neuropathy', or 'microvascular' and 'cardiovascular disease', 'stroke', 'coronary heart disease' or 'peripheral vascular disease' and 'type 2 diabetes' and MESH equivalents. Prospective studies with at least 200 type 2 diabetes subjects that evaluated hard cardiovascular endpoints were selected. In 25 studies (n=54,117) included in the review there was evidence of an association between microvascular complications (notably retinopathy or nephropathy) and cardiovascular events. Diabetic retinopathy was associated with ∼ 1.7-fold increased risk for cardiovascular events, and albuminuria or reduced GFR associated with ∼ two-fold increased risk for cardiovascular events. In the presence of more than one complication, this risk was accentuated. These associations remained even after adjustment for conventional cardiovascular risk factors, diabetes duration and glycaemic control. These data suggest that similar mechanisms may be relevant to the pathogenesis of both micro- and macrovascular disease in type 2 diabetes. It is likely that endothelial dysfunction, low-grade inflammation and rheological abnormalities are common mechanistic denominators. CONCLUSIONS: This review highlights the association between micro- and macrovascular disease in type 2 diabetes, underlining the importance of early detection of microangiopathy for vascular risk assessment in type 2 diabetes.

Medical management of diabetic retinopathy: fenofibrate and ACCORD Eye studies.

The approach of all ophthalmologists, diabetologists and general practitioners seeing patients with diabetic retinopathy should be that good control of blood glucose, blood pressure and plasma lipids are all essential components of modern medical management. The more recent data on the use of fenofibrate in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye studies is reviewed. In FIELD, fenofibrate (200 mg/day) reduced the requirements for laser therapy and prevented disease progression in patients with pre-existing diabetic retinopathy. In ACCORD Eye, fenofibrate (160 mg daily) with simvastatin resulted in a 40% reduction in the odds of retinopathy progressing over 4 years, compared with simvastatin alone. This occurred with an increase in HDL-cholesterol and a decrease in the serum triglyceride level in the fenofibrate group, as compared with the placebo group, and was independent of glycaemic control. We believe fenofibrate is effective in preventing progression of established diabetic retinopathy in type 2 diabetes and should be considered for patients with pre-proliferative diabetic retinopathy and/or diabetic maculopathy, particularly in those with macular oedema requiring laser.

Does renin-angiotensin system blockade have a role in preventing diabetic retinopathy? A clinical review.

Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates to treatment rather than prevention of disease. Tight glycaemic and blood pressure control helps to reduce the risk of retinopathy, but this is not easy to achieve in practice and additional treatments are needed for both primary and secondary prevention of retinopathy. A renin-angiotensin system (RAS) has been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril. The clinical implications of these new data are discussed.

Diabetic retinopathy and blockade of the renin-angiotensin system: new data from the DIRECT study programme.

The pathogenesis and medical management of diabetic retinopathy is reviewed. The importance of good control of blood glucose and blood pressure remain key elements in the prevention and treatment of diabetic retinopathy, and a number of specific metabolic pathways have been identified that may be useful additional targets for therapeutic intervention. Trial data, however, aimed specifically to answer the questions of optimum medical management are limited, so the DIRECT study of renin-angiotensin blockade using oral candesartan 32 mg daily is a welcome addition to our knowledge. This arose from the promising improvement of retinopathy outcomes in the EUCLID study of lisinopril in type I diabetes. In DIRECT, 5 years of candesartan treatment in type I diabetes reduced the incidence of retinopathy by two or more steps (EDTRS) in severity by 18% (P=0.0508) and, in a post hoc analysis, reduced the incidence of retinopathy by three-step progression by 35% (P=0.034). In type I diabetes patients there was no effect on progression of established retinopathy. In contrast, in type II diabetes, 5 years of candesartan treatment resulted in 34% regression of retinopathy (P=0.009). Importantly, an overall significant change towards less-severe retinopathy was noted in both type I and II diabetes (P

Sputum IL-5 concentration is associated with a sputum eosinophilia and attenuated by corticosteroid therapy in COPD.

BACKGROUND: Airway inflammation in chronic obstructive pulmonary disease (COPD) is predominately neutrophilic, but some subjects demonstrate eosinophilic airway inflammation. Whether these inflammatory phenotypes have differential cytokine and chemokine expression is unknown. OBJECTIVES: To assess the sputum concentrations of cytokines and chemokines and their response to oral corticosteroid therapy in COPD subjects with or without a sputum eosinophilia. METHODS: Cytokine and chemokine concentrations were measured using the meso-scale device platform. To assess validity, recovery of exogenous spikes was examined. The concentrations of the validated mediators were measured in COPD sputum from subjects with or without a sputum eosinophilia. In a subgroup with a sputum eosinophilia, the response to oral prednisolone 10 mg for 1 month was examined. RESULTS: The recovery in sputum of exogenous spiked mediators was >80% in 11/26 cytokines and chemokines. In supernatants from eosinophilic (n = 39) versus non-eosinophilic (n = 59) sputa, the geometric mean (95% CI) concentration was increased for IL-5 [9.0 (4.5-18) pg/ml vs. 3.6 (2.7-6.3) pg/ml, p = 0.03]. IL-5 alone was correlated with sputum eosinophil counts (r = 0.33, p = 0.001), and was attenuated following treatment with prednisolone [n = 9; mean difference 2.3 pg/ml (0.2-4.3), p = 0.032]. CONCLUSION: We have validated the use of the meso-scale device platform for cytokine and chemokine measurements in the sputum supernatants in COPD. Sputum IL-5 was associated with a sputum eosinophilia and was attenuated following oral corticosteroid therapy. Whether this cytokine is important in the pathogenesis of COPD in a subgroup of patients warrants further investigation.

Management of diabetic retinopathy: could lipid-lowering be a worthwhile treatment modality?

Diabetic eye disease confers substantial burden on the patient quality of life. Current therapeutic strategies indicate an unmet clinical need for preventive therapy. Tight control of blood pressure and glycaemia are mandatory components of primary prevention strategies, but are insufficient to eliminate risk in all patients. A body of evidence supports a role for lipid-modifying therapy in reducing the diabetic retinopathy endpoints. Although inconclusive for statin therapy, results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study show beneficial effects of fenofibrate in reducing the requirement for laser therapy, and particularly in preventing disease progression in patients with pre-existing diabetic retinopathy. However, there is a need for confirmation of these findings in large prospective studies with progression of retinopathy as the primary endpoint, such as the ACCORD-EYE (Action to Control Cardiovascular Risk in Diabetes-EYE) study, and in a clinical trial specifically conducted for diabetic maculopathy. In addition, elucidation of the mechanism(s) of effect of fenofibrate is indicated.

Homocysteine, folates, and the eye.

Plasma homocysteine has been identified as a risk factor for arterial disease, retinal artery and vein occlusions, and other common eye diseases. The value of treating an elevated plasma homocysteine with folic acid for preventing further vascular disease has not been proven. Although secondary prevention of coronary artery disease using this approach has been unsuccessful, trials on primary prevention of stroke and loss of cognitive function with folic acid supplementation appear to be successful. Further trial data are awaited. In patients with premature retinovascular disease, the measurement of plasma homocysteine is suggested and reduction of elevated homocysteine with folic acid for secondary prevention of retinal arterial and venous occlusion. Meanwhile, the debate on fortification of flour for primary prevention of neural tube defects, which has already taken place in North America, continues in European countries. Such fortification could have an impact on primary and secondary prevention of vascular disease.

Pain response and follow-up of patients undergoing panretinal laser photocoagulation with reduced exposure times.

PURPOSE: We performed a study of laser panretinal photocoagulation in 20 patients with proliferative retinopathy. We compared short exposure, high-energy laser settings with conventional settings, using a 532 nm, frequency doubled, Neodymium-Yag laser and assessed the patients in terms of pain experienced and effectiveness of treatment. METHODS: Twenty patients having panretinal photocoagulation for the first time underwent random allocation to treatment of the superior and inferior hemi-retina. Treatment A used 'conventional' parameters: exposure time 0.1 s, power sufficient to produce a visible grey-white burns, spot size 300 microm. The other hemi- retina was treated with treatment B using exposure 0.02 s, 300 microm and sufficient power to have similar endpoint. All patients were asked to evaluate severity of pain on a visual analogue scale. (0=no pain, 10=most severe pain). All patients were masked as to the type of treatment and the order of carrying out the treatment on each patient was randomised. Patients underwent fundus photography and were followed up for 6-45 months. RESULTS: Seventeen patients had proliferative diabetic retinopathy, two had ischaemic central retinal vein occlusion and one had ocular ischaemic syndrome. The mean response to treatment A was 5.11, compared to 1.40 treatment B, on the visual analogue scale, which was statistically significant (P=0.001). All patients preferred treatment B. Further treatments, if required, were performed with treatment B parameters and long-term follow-up has shown no evidence of undertreatment. CONCLUSIONS: Shortening exposure time of retinal laser is significantly less painful but equally effective as conventional parameters.

Basis of the gabamimetic profile of ethanol.

This article summarizes the proceedings of a symposium held at the 2005 Research Society on Alcoholism meeting. The initial presentation by Dr. Wallner provided evidence that selected GABA(A) receptors containing the delta subunit display sensitivity to low intoxicating ethanol concentrations and this sensitivity is further increased by a mutation in the cerebellar alpha6 subunit, found in alcohol-hypersensitive rats. Dr. Mameli reported that ethanol affects gamma-aminobutyric acid (GABA) function by affecting neural circuits that influence GABA release. Dr. Parsons presented data from electrophysiological and microdialysis investigations that ethanol is capable of releasing GABA from presynaptic terminals. Dr. Morrow demonstrated that systemic ethanol increases neuroactive steroids in brain, the absence of which alters various functional responses to ethanol. Dr. Criswell presented evidence that the ability of ethanol to increase GABA was apparent in some, but not all, brain regions indicative of regional specificity. Further, Dr. Criswell demonstrated that neurosteroids alone and when synthesized locally by ethanol act postsynaptically to enhance the effect of GABA released by ethanol in a region specific manner. Collectively, this series of reports support the GABAmimetic profile of acutely administered ethanol being dependent on several specific mechanisms distinct from a direct effect on the major synaptic isoforms of GABA(A) receptors.