Diabete melito é umas das principais endocrinopatias, caracterizada pela deficiência relativa ou absoluta de insulina, que pode resultar em diversas manifestações oculares, sendo as mais frequentes a retinopatia diabética e a catarata. Retinopatia diabética (RD) é uma microangiopatia que afeta primeiramente as arteríolas pré-capilares, capilares, vênulas pós-capilares e vasos de maior calibre, causando incompetência funcional e anatômica dos vasos retinianos. A hiperglicemia pode ser a causa mais provável da lesão retiniana, interferindo nas vias de metabolismo celular e no processo de transdução. Os achados fundoscópicos incluem: microaneurismas, dilatação e tortuosidade das vênulas retinianas, hiper-refletividade da área tapetal e exsudatos coriorretinianos. Como a catarata impossibilita a fundoscopia, a prevalência da retinopatia diabética nos cães não esta totalmente esclarecida, sugerindo que esta seja na forma não proliferativa. Objetivou-se neste estudo, determinar a prevalência das alterações fundoscópicas relacionadas à retinopatia diabética em cães, com auxílio de documentação fotográfica (retinografia) e tomografia de coerência óptica (OCT). Vinte e dois cães diabéticos, 18 fêmeas e quatro machos, com idade variando de seis a 15 anos, provenientes do Serviço de Oftalmologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, foram submetidos a acompanhamento por meio da retinografia durante o período de 12 meses. Para realização do exame de OCT foram selecionados oito cães dos 22 animais avaliados, quatro fêmeas e quatro machos, com idades variando de seis a 15 anos para compor o grupo diabete melito (GDM), e nove cães sendo cinco fêmeas e quatro machos, com idades entre quatro e 15 anos, sem quaisquer alterações oculares e não diabéticos formaram o grupo controle (GCO). Os cães diabéticos acompanhados durante 12 meses apresentaram alteração vascular, microaneurismas e hemorragias, e alterações na coloração e refletividade da área tapetal. Sendo que dois cães, dos 22 animais avaliados, apresentaram hemorragia em mancha no último período de avaliação, e um cão apresentou focos hemorrágicos durante todo o período de avaliação. A espessura e arquitetura retiniana realizada pela OCT nos cães diabéticos, demonstrou afinamento das camadas da retina e perda da estratificação em comparação com os animais controle (198 µm versus 219 µm, respectivamente), sendo esta redução estatisticamente significante. Com os achados retinográficos deste estudo podemos confirmar que as lesões são compatíveis com a RD não proliferativa sem comprometimento visual, e baseado nas imagens da OCT pode-se sugerir que a diabete melito, no cão, cause neuropatia retiniana como descrito em humanos diabéticos / Diabetes mellitus is one of the most frequent endocrine disorders, characterized by relative or absolute deficiency of insulin, which can induces several ocular manifestations, among them diabetic retinopathy and cataract. Diabetic Retinopathy is a microangiopathy that affects the precapillary, arterioles, capillaries, postcapillary venules, and the large vessels, causing them to be functionally and anatomically incompetent. Hyperglycemia seems to be the most probably cause of retinal damage, interfering in the cellular metabolism process and in transduction process. The fundoscopic findings are microaneurysm, retinal venular dilatation and tortuosity, hyperreflectivity of tapetal area and chorioretinal exsudates. Because the cataract precludes fundoscopic examination, the diagnosis of diabetic retinopathy in dogs is not completely elucidated, but suggests that disease is nonproliferative form. The aim of this study was to determine the prevalence of fundus changes related to diabetic retinopathy in dogs, with photography documentation (fundus camera) and optical coherence tomography (OCT). Twenty-two diabetic dogs, 18 females and four males, from six to 15 years, from Serviço de Oftalmologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, underwent monitoring by retinography during the period 12 months. For the OCT examination were selected eight dogs of the 22 evaluated animals, four females and four males, from six to 15 years formed the group diabetes mellitus (GDM), and nine dogs with five females and four males, from 4 to 15 years, with no ocular alterations and non-diabetic formed the control group (GC). Diabetic dogs followed for 12 months showed vascular changes, microaneurisms and hemorrhage, and changes in colour and reflections of tapetal area. Two dogs, among the 22 animals studied, presented hemorrhage stain in the last period, and one dog presented hemorrhage focus throughout the evaluation period. The thickness and retinal architecture performed by OCT in diabetic dogs showed thinning of the retinal layers with loss of stratification compared to control animals (198 µm versus 219 µm, respectively), with a statistically significant difference. Based on fundus findings of this study we can confirm that the lesions are compatible with DR nonproliferative without visual impairment. The OCT images may suggest that diabetes mellitus in the dog causes retinal neuropathy as described in diabetic humans

Diabete melito é umas das principais endocrinopatias, caracterizada pela deficiência relativa ou absoluta de insulina, que pode resultar em diversas manifestações oculares, sendo as mais frequentes a retinopatia diabética e a catarata. Retinopatia diabética (RD) é uma microangiopatia que afeta primeiramente as arteríolas pré-capilares, capilares, vênulas pós-capilares e vasos de maior calibre, causando incompetência funcional e anatômica dos vasos retinianos. A hiperglicemia pode ser a causa mais provável da lesão retiniana, interferindo nas vias de metabolismo celular e no processo de transdução. Os achados fundoscópicos incluem: microaneurismas, dilatação e tortuosidade das vênulas retinianas, hiper-refletividade da área tapetal e exsudatos coriorretinianos. Como a catarata impossibilita a fundoscopia, a prevalência da retinopatia diabética nos cães não esta totalmente esclarecida, sugerindo que esta seja na forma não proliferativa. Objetivou-se neste estudo, determinar a prevalência das alterações fundoscópicas relacionadas à retinopatia diabética em cães, com auxílio de documentação fotográfica (retinografia) e tomografia de coerência óptica (OCT). Vinte e dois cães diabéticos, 18 fêmeas e quatro machos, com idade variando de seis a 15 anos, provenientes do Serviço de Oftalmologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, foram submetidos a acompanhamento por meio da retinografia durante o período de 12 meses. Para realização do exame de OCT foram selecionados oito cães dos 22 animais avaliados, quatro fêmeas e quatro machos, com idades variando de seis a 15 anos para compor o grupo diabete melito (GDM), e nove cães sendo cinco fêmeas e quatro machos, com idades entre quatro e 15 anos, sem quaisquer alterações oculares e não diabéticos formaram o grupo controle (GCO). Os cães diabéticos acompanhados durante 12 meses apresentaram alteração vascular, microaneurismas e hemorragias, e alterações na coloração e refletividade da área tapetal. Sendo que dois cães, dos 22 animais avaliados, apresentaram hemorragia em mancha no último período de avaliação, e um cão apresentou focos hemorrágicos durante todo o período de avaliação. A espessura e arquitetura retiniana realizada pela OCT nos cães diabéticos, demonstrou afinamento das camadas da retina e perda da estratificação em comparação com os animais controle (198 µm versus 219 µm, respectivamente), sendo esta redução estatisticamente significante. Com os achados retinográficos deste estudo podemos confirmar que as lesões são compatíveis com a RD não proliferativa sem comprometimento visual, e baseado nas imagens da OCT pode-se sugerir que a diabete melito, no cão, cause neuropatia retiniana como descrito em humanos diabéticos / Diabetes mellitus is one of the most frequent endocrine disorders, characterized by relative or absolute deficiency of insulin, which can induces several ocular manifestations, among them diabetic retinopathy and cataract. Diabetic Retinopathy is a microangiopathy that affects the precapillary, arterioles, capillaries, postcapillary venules, and the large vessels, causing them to be functionally and anatomically incompetent. Hyperglycemia seems to be the most probably cause of retinal damage, interfering in the cellular metabolism process and in transduction process. The fundoscopic findings are microaneurysm, retinal venular dilatation and tortuosity, hyperreflectivity of tapetal area and chorioretinal exsudates. Because the cataract precludes fundoscopic examination, the diagnosis of diabetic retinopathy in dogs is not completely elucidated, but suggests that disease is nonproliferative form. The aim of this study was to determine the prevalence of fundus changes related to diabetic retinopathy in dogs, with photography documentation (fundus camera) and optical coherence tomography (OCT). Twenty-two diabetic dogs, 18 females and four males, from six to 15 years, from Serviço de Oftalmologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, underwent monitoring by retinography during the period 12 months. For the OCT examination were selected eight dogs of the 22 evaluated animals, four females and four males, from six to 15 years formed the group diabetes mellitus (GDM), and nine dogs with five females and four males, from 4 to 15 years, with no ocular alterations and non-diabetic formed the control group (GC). Diabetic dogs followed for 12 months showed vascular changes, microaneurisms and hemorrhage, and changes in colour and reflections of tapetal area. Two dogs, among the 22 animals studied, presented hemorrhage stain in the last period, and one dog presented hemorrhage focus throughout the evaluation period. The thickness and retinal architecture performed by OCT in diabetic dogs showed thinning of the retinal layers with loss of stratification compared to control animals (198 µm versus 219 µm, respectively), with a statistically significant difference. Based on fundus findings of this study we can confirm that the lesions are compatible with DR nonproliferative without visual impairment. The OCT images may suggest that diabetes mellitus in the dog causes retinal neuropathy as described in diabetic humans

"January 2003." Bibliography: 10.1-10.11 leaves. This thesis presents results from the Katherine Region Diabetic Retinopathy Study (1993-1996). These results provide the first detailed information on the basic epidemiology of diabetic retinopathy and impaired vision in an Aboriginal diabetic population.

Master of Public Health / OBJECTIVES: In Australia, diabetes causes significant morbidity and mortality. Whilst the need to prevent diabetes and its complications has been widely recognised, the capacity of health care systems - which organise diabetes care - to facilitate prevention has not been fully established. METHODS: A series of seven population-based case-control studies were used to examine the effectiveness of the Australian health care system and its capacity to manage diabetes. Six of the studies compared the patterns of care of patients who had developed advanced diabetes complications in 2000 (cases), to similar patients who remained free of the condition (controls) across Australia and for various risk groups. A secondary study investigated the role of treating GPs in the development of the outcome. RESULTS: A strong relationship between the patterns of care and the development of advanced diabetes complications was found and is described in Chapter 4. In Chapter 5, this same relationship was investigated for each Australian state and territory, and similar findings were made. The study in Chapter 6 investigated whether late diagnosis or the patterns of care was the stronger risk factor for advanced diabetes complications, finding that the greatest risk was associated with the latter. In Chapter 7 the influence of medical care during the pre-diagnosis period was explored, and a strong relationship between care obtained in this period and the development of advanced complications was found. In Chapter 8, which investigated the role of socio-economic status in the development of advanced complications, found that the risk of advanced diabetes complications was higher in low socio-economic groups. Chapter 9 investigated geographic isolation and the development of advanced diabetes complications and found that the risk of advanced complications was higher in geographically isolated populations. Finally, Chapter 10, which utilised a provider database, found that some GP characteristics were associated with the development of advanced diabetes complications in patients. CONCLUSION: A number of major risk factors for the development of advanced complications in Australia was found. These related to poorer diabetes management, later diagnosis, low socioeconomic status and geographic isolation. Strategies must be devised to promote effective diabetes management and the early diagnosis of diabetes across the Australian population.

"January 2003." / Bibliography: 10.1-10.11 leaves. / 1 v. : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis presents results from the Katherine Region Diabetic Retinopathy Study (1993-1996). These results provide the first detailed information on the basic epidemiology of diabetic retinopathy and impaired vision in an Aboriginal diabetic population. / Thesis (Ph.D.)--University of Adelaide, Dept. of Public Health, 2003

To ensure that the resources of the health care sector are used effectively, new technologies need to be evaluated before implementation to examine if they generate health outcomes at an acceptable cost. This information can be collected by performing health economic evaluations in which the costs and health outcomes of different technologies are compared. To estimate the effect on health care budgets, there is also a need for information about the prevalence of the specific disease. Health outcomes in health economic evaluations are often measured in quality-adjusted life years (QALYs), which are calculated by multiplying the remaining life years after an intervention by a weight representing the health-related quality of life (HRQoL) during those years. This thesis aims to provide deeper knowledge of the health economic aspects of diabetic retinopathy (DR), an eye complication that affects patients with diabetes and may in the worst case lead to blindness. The focus is on three empirical and two methodological health economic research questions. The empirical research areas cover prevalence, costs, and HRQoL related to patients with DR. The methodological research questions explore the performance of different methods for estimation of QALY weights. This is of interest since it has been argued that the most common methods for estimating QALY weights may not capture all relevant vision-related aspects of quality of life. The analyses comprehend the validity of different methods for estimating QALY weights among patients with DR and if the results of one of the specific methods for estimating QALY weights, the time trade-off (TTO) exercise, are affected by patients’ subjective life expectancy (SLE). The empirical results demonstrate that DR is seen in approximately 40% and 30% of patients with type I and type II diabetes respectively, indicating that the prevalence of DR has decreased in both of these patient groups. Healthcare costs vary considerably between different severity levels of the disease, being estimated at €26, €257, €216, and €433 per patient per year for background retinopathy, proliferative diabetic retinopathy (PDR), diabetic macular oedema (DMO), and PDR combined with DMO respectively. Blindness due to DR is associated with an increased use of transportation services, caregiving services, and assistive technologies as well as productivity losses. This suggests that preventing the progression of DR may lower healthcare costs. Patients with vision impairment due to DR have lowered HRQoL in various dimensions, but the diagnosis of DR in itself has only a limited effect on HRQoL. The results on the methodological research questions show that different methods for estimating QALY weights seem to give different results. In comparison to EQ-5D, the Health Utilities Index Mark 3 (HUI-3) is the most sensitive method for detecting differences in QALY weights due to DR, and if decisions are to be made based on values from the general public, it can be recommended for use in cost-utility analyses of interventions directed at DR. Neither of the direct methods, TTO and the visual analogue scale, seems to be sensitive to differences in visual function, and more research is needed concerning the role of vision in people’s responses to the TTO exercises. In TTO exercises with time frames based on actuarial life expectancy, the patients’ SLE has an effect on their willingness to trade off years for full health. Thus, applying time frames deviating from patients’ SLE may result in biased QALY weights. Such bias may appear stronger within patient populations than within the general public. In conclusion, this thesis offers estimates for prevalence, costs, and QALY weights that can be used in economic evaluations of interventions directed at DR and as benchmarks for future DR research in order to follow up consequences of changes in diabetes care. In addition, it demonstrates that the choice of method for estimating QALY weights may have an impact on whether an intervention is considered cost-effective.

Background/aim. The incidence of microvascular complications has been reported to be unchanged the last decades. However, in randomized clinical trials it has been shown that improved metabolic control can reduce the development of long term complications. It has been debated whether it is possible to achieve the same results in an unselected population. In a previous study we found a decreased incidence of overt nephropathy, but unchanged incidence of severe laser treated retinopathy in a population of patients with type 1 diabetes diagnosed in childhood. The aim of the present study was to investigate the incidence 10 years later in the same population and to analyse the importance of possible risk factors. In another previous study we found a high prevalence of subclinical neuropathy among young diabetic patients despite intensive insulin therapy since diagnosis. The aim of the present study was to examine if intensive treatment is more effective in preventing early diabetic complications other than neuropathy. The incidence of type 1 diabetes has doubled in Sweden the last decades. The reason must be environmental factors. These, as well as more intensive insulin regimens from onset of diabetes, might also lead to different disease process. We wanted to analyse if clinical characteristics at onset had changed the last 25 years and if there was any secular trend of C-peptide secretion. We also intended to investigate if longer persistence of C-peptide secretion could be of importance for prevention of long term complications. Methods. The whole study population consisted of all 478 patients with type 1 diabetes diagnosed before the age of 15 during the years 1961 - 2000, living in the catchment area of the Paediatric Clinic, University Hospital, Linköping, Sweden. For the statistical analysis the population was divided into five–year cohorts according to time of onset of diabetes. The cumulative proportion of severe retinopathy and overt nephropathy in 269 patients with onset of diabetes 1961 - 1985 was computed with survival analysis. Multivariable regression models were used to analyse the importance of metabolic control, diabetes duration, blood pressure, smoking, BMI, lipids and persisting C-peptide secretion. The prevalence of all grades of retinal changes, nephropathy and neuropathy, defined as abnormal nerve conduction, was estimated in the late 1990s in a subgroup of 80 children and adolescents with mean 13 years of diabetes duration. Clinical characteristics at onset, duration of partial remission and regularly measurements of fasting and stimulated C-peptide secretion the first five years after onset were analysed in 316 patients with onset of diabetes 1976 - 2000. Results. The cumulative proportion of severe laser treated retinopathy showed a significant declining trend the last decades. The decrease was significant between the oldest cohort with diabetes onset 1961 - 1965 and the cohorts with diabetes onset 1971 - 1975 and 1976 - 1980. The cumulative proportion of overt nephropathy also declined with a significant decrease between the oldest cohorts and all the following cohorts. After 25 years of diabetes duration it was 30% and 8% in the two oldest cohorts respectively and remained largely unchanged after 30 years. Diabetes duration and long term HbA1c were the only significant independent risk factors for both retinopathy and nephropathy. The risk of overt nephropathy increased substantially when HbA1c was above 8.5%, while the risk of severe retinopathy increased already when HbA1c exceeded 7.5%. The prevalence of neuropathy was 59%, of retinopathy 27% and of nephropathy 5% in the population of young patients after mean 13 years of diabetes duration. During the last 25 years the clinical characteristics at onset were unchanged as well as duration of partial remission and magnitude and persistence of C-peptide secretion. Conclusions. In this unselected population the cumulative proportion of severe retinopathy and overt nephropathy decreased over the last decades. Diabetic nephropathy has probably been prevented and not just postponed. Good glycaemic control was the most important factor to avoid complications, with the necessity of a lower level of HbA1c to escape retinopathy than nephropathy. Intensive insulin regimens from diabetes onset was not sufficient to entirely escape early diabetic complications after mean 13 years of diabetes duration, even if the prevalence of retinopathy and especially nephropathy was lower than usually reported. The clinical picture at onset of diabetes was unchanged the last 25 years. There was no secular trend of partial diabetes remission or C-peptide secretion during the first years after diagnosis.

Current anti-VEGF biologics, such as bevacizumab and VEGF trap, have been successfully used as therapeutic agents for cancer and age-related macular degeneration (AMD). Since these strategies target VEGF systemically, their toxicity profile, including proteinuria and thromboembolic events, and need for frequent eye injections in AMD treatment, prevail. Therefore, the aim of this PhD thesis was to generate novel anti-VEGF biologics that inhibit VEGF activity specifically at the desired target site. Two classes of biologics were engineered that simultaneously bind VEGF and either: 1) the extracellular matrix (ECM) or 2) target-site specific antigens. The first subgroup, “sticky-traps”, is composed of VEGF trap linked to a sequence of hydrophobic amino acids, with affinity for heparin sulfate proteoglycans of the ECM. The second subgroup, “lassos”, is composed of a C-terminus positioned form of VEGF trap linked to single-chain variable domain antibodies specific for either HER2 (HER2/V lasso) or fibronectin extra domain B (EDB; EDB/V lasso), expressed on breast cancer cell surfaces or in the vascular bed of solid tumours, respectively. ii Using a novel transgenic method, piggyBac transposons, biologics were expressed in transgenic cancer cell lines in a doxycycline inducible manner. They were shown to inhibit VEGF activity and also retain the native function of their constituent domains. Specifically, the sticky-traps adhered to the ECM and the HER2/V lasso inhibited the proliferation of HER2 positive cancer cell lines. Sticky-traps as well as lassos were able to inhibit or delay tumour growth of A-673, Pc-3, SKOV-3 and HT-29 xenografts. In contrast to soluble VEGF trap, sticky-traps were retained at the tumour site and were undetectable in the circulation. Moreover, sticky-traps, in contrast to VEGF trap, did not delay wound healing and regression of trachea blood vessels. Furthermore, transgenic studies indicated that HER2/V lasso is more effective compared to anti-HER2 Ab and VEGF trap used alone or in combination. These novel classes of antiangiogenic molecules could be advantageous in a clinical setting. Using the principles established in my PhD thesis work, similar dual function biologics can be designed for inhibition of other molecules with disease relevance.

Current anti-VEGF biologics, such as bevacizumab and VEGF trap, have been successfully used as therapeutic agents for cancer and age-related macular degeneration (AMD). Since these strategies target VEGF systemically, their toxicity profile, including proteinuria and thromboembolic events, and need for frequent eye injections in AMD treatment, prevail. Therefore, the aim of this PhD thesis was to generate novel anti-VEGF biologics that inhibit VEGF activity specifically at the desired target site. Two classes of biologics were engineered that simultaneously bind VEGF and either: 1) the extracellular matrix (ECM) or 2) target-site specific antigens. The first subgroup, “sticky-traps”, is composed of VEGF trap linked to a sequence of hydrophobic amino acids, with affinity for heparin sulfate proteoglycans of the ECM. The second subgroup, “lassos”, is composed of a C-terminus positioned form of VEGF trap linked to single-chain variable domain antibodies specific for either HER2 (HER2/V lasso) or fibronectin extra domain B (EDB; EDB/V lasso), expressed on breast cancer cell surfaces or in the vascular bed of solid tumours, respectively. ii Using a novel transgenic method, piggyBac transposons, biologics were expressed in transgenic cancer cell lines in a doxycycline inducible manner. They were shown to inhibit VEGF activity and also retain the native function of their constituent domains. Specifically, the sticky-traps adhered to the ECM and the HER2/V lasso inhibited the proliferation of HER2 positive cancer cell lines. Sticky-traps as well as lassos were able to inhibit or delay tumour growth of A-673, Pc-3, SKOV-3 and HT-29 xenografts. In contrast to soluble VEGF trap, sticky-traps were retained at the tumour site and were undetectable in the circulation. Moreover, sticky-traps, in contrast to VEGF trap, did not delay wound healing and regression of trachea blood vessels. Furthermore, transgenic studies indicated that HER2/V lasso is more effective compared to anti-HER2 Ab and VEGF trap used alone or in combination. These novel classes of antiangiogenic molecules could be advantageous in a clinical setting. Using the principles established in my PhD thesis work, similar dual function biologics can be designed for inhibition of other molecules with disease relevance.

This study aims to identify the perceived barriers to eye care and to evaluate concerns about vision and eye care among patients with diabetes in the greater New Haven area. A qualitative study applying one-on-one semi-structured interviews and non-participatory observations was conducted to identify the factors that deter diabetics from seeking eye care. Patients were recruited at the Yale Primary Care Center, Diabetes Center and Eye Center, who met the following criteria: 1) have been diagnosed with type 1 or type 2 diabetes and 2) have been referred to an eye center for dilated eye exam and/or treatment. All interviews and discussions were recorded and transcribed. The transcripts were then analyzed to detect recurrent themes. Data collection continued until no new themes emerged. This study showed that lack of awareness and lack of adequate referral to regular diabetic eye exam were viewed as the most common barriers. Many patients had limited awareness that diabetes could affect the eye or lead to blindness. Patients had little knowledge of diabetic retinopathy, or the significance of early screening and intervention. Primary care providers usually emphasized diet and blood sugar control to prevent future complications; diabetic eye care education was not often prioritized. Other barriers included cost, lack of insurance, immobility due to diabetic complications, reluctance to receive medical intervention, and distrust of the services. A strong family history of diabetes and blindness due to diabetes contributed to the awareness of diabetic retinopathy, and as a result motivated patients to seek regular eye care. Raising the awareness of diabetic retinopathy and the risk of vision loss, offering more diabetic eye care education, tracking the status of patients eye exam attendance, and providing adequate eye exam referral to a patient friendly eye clinic may encourage diabetics to attend regular eye exams.