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.

Although very low birth weight preterm (VLBW) infants with grade 3,4 retinopathy of prematurity (ROP) are at high risk for unfavorable visual outcomes, the middle school vision motor integration (VMI) skills and cognitive outcome scores of these children remain largely unknown. Data for 323 very VLBW survivors of the Multicenter Randomized Indomethacin IVH Prevention Trial (BW 600 1250 g) were analyzed to test the hypothesis that grades 3, 4 ROP would be an important predictor of cognitive and VMI skills. 3 subgroups were evaluated: ROP negative (N = 163), ROP grades 1,2 (N = 137) and ROP grades 3,4 (N = 23) were evaluated prospectively at 12 years of age with a neurocognitive battery. High-resolution volumetric MRI scans were quantified for 40 of the study subjects, and occipital brain volumes were correlated with Beery VMI scores. Children with ROP 3-4 had [arrow up - increased] vision impairment and lower test scores. Whole brain volumes were significantly less for children with any grade of ROP (p = 0.02), occipital white matter volumes tended to be less for the same study subjects (p = 0.08) and both total occipital brain volumes and occipital white matter volumes were significantly correlated with Beery VMI scores (r=0.610, p = 0.009 and r = 0.652, p =0.005, respectively). Prematurely-born children with a history of grade 3-4 ROP continue to have [arrow up - increased] vision impairment, special needs and lower performance on cognitive, language and visual motor integration scores at age 12 years. Both whole occipital brain volumes and occipital white matter volumes were predictive of VMI scores for children with ROP. (supp by NS 27116)

People with diabetes are at double the risk of developing depression. Depression is associated with increased morbidity and mortality in people with diabetes. Levels of A1c have been linked to microvascular complications (e.g., retinopathy, nephropathy, and neuropathy) as well as depression. The interrelationship between A1c, microvascular complications, and depression has not previously been investigated in a comprehensive model, and a better understanding of the nature of these associations is needed. Preliminary analyses test the assumption that A1c mediates the relationship between group assignment in the Diabetes Control and Complications Trial (DCCT) and microvascular complications. The primary purpose of the study is to examine multiple mediation models, which hypothesize that the severity of microvascular complications mediates the relationship between A1c and depressive symptomatology levels. Participants were people with type 1 diabetes (N = 1441) enrolled in the DCCT, a longitudinal randomized controlled trial investigating intensive insulin treatment and diabetes complications, and divided into primary (e.g., no retinopathy) and secondary (e.g., mild retinopathy) cohorts. Biological markers were used to measure A1c and microvascular complications. Depressive symptomatology was measured by the depression subscale of the Symptom Checklist-90-Revised. Simple and multiple mediation analyses were used to test proposed models. A1c mediates the relationship between DCCT group assignment and microvascular complications. Microvascular complications partially mediate the relationship between A1c and depression for the full sample and secondary cohort. Results support the hypothesis that the severity of microvascular complications, in part, accounts for the association between A1c and depressive symptomatology in people with type 1 diabetes.

Diabetes affects more than 382 million people worldwide and can lead to vision loss as a result of progressive degeneration of the neurovascular unit in the retina, a condition known as diabetic retinopathy (DR). Early stage DR is characterized by microangiopathies including microaneurysms, microhemorrhages, and hyperpermeability. Analyses of postmortem human retinal tissue and retinas from animal models indicate that degeneration of the pericytes, the cells that make up the outer layer of capillaries, is an early event in DR; however, the relative contribution of specific cellular components to DR pathobiology has been difficult to dissect due to the complexity of existing models.

The aim of this study was to determine management regimens and level of knowledge of diabetes and its‟ ocular complications among private patients in a sample of the population of the Western Cape region of South Africa. A population-based cross-sectional study design, using purposive accidental random sampling, was used. Questionnaires completed by diabetic patients who fund their condition privately outside of the South African Public Health sector were used. One hundred and twenty-two subjects participated in the research, 66 (54%) males and 56 (46%) females. There were 73 rural and 49 urban participants. The overall sample mean BMI was 30.7, average fasting plasma glucose (FPG) 8.1 mmol/l and the majority of respondents did not perform a daily FPG test or know the significance of the HbA1c test. The majority of participants were unaware of the serious ocular consequences of prolonged hyperglycaemia. Sixty-seven percent of respondents considered that they knew enough about diabetes to manage their own condition. From the data it is apparent that private patients‟ knowledge of the systemic and ocular complications of diabetes is sub-optimal. Whilst the majority considered annual eye examinations as important, less than one-third of respondents actually undertook them. Optometrists should be offered programmes to enhance their skills and co-manage and educate diabetic patients with other health care practitioners on a formal basis. Health insurance institutions should take cognisance of the value of patient education and preventative diabetic management and incentivize patients and health care providers in this regard. / Thesis (M.Optom.)-University of KwaZulu-Natal, Westville, 2011.

Antalet patienter med sjukdomen diabetes förväntas öka vilket kommer innebära att ett ännu större antal patienter behöver screenas för att upptäcka diabetesretinopati. Syftet med den här pilotstudien var att beskriva patienters erfarenheter av screening för diabetesretinopati på en ögonmottagning. Pilotstudien utformades efter en kvalitativ induktiv ansats och data samlades in genom semistrukturerade intervjuer. Materialet bearbetades genom kvalitativ innehållsanalys. De huvudkategorier som framkom var: trygghet, informationens betydelse, tillgänglighetens betydelse, oro för undersökningsresultatet och dess konsekvenser samt obehagligt och tidskrävande. Resultatet visade på att det var viktigt för informanterna med screening för diabetesretinopati. Det var en trygghet att få gå på kontroller för att upptäcka komplikationer i tid. Det framkom att de kände en oro för att utveckla diabetesretinopati och vilken påverkan detta skulle ha på deras livssituation. Informanterna ville få ett tydligare resultat från undersökningen och att tillgängligheten förbättrades.  Det behövs vidare omvårdnadsforskning kring information, kunskap och ökad tillgänglighet vid screening för diabetesretinopati. Sådan forskning kommer att vara till hjälp för att förstå och därmed hitta strategier för att förbättra omvårdnaden för patienter med diabetes samt för att nå ut till dem som uteblir från screeningen för diabetesretinopati. / The number of patients with the disease diabetes expects to increase, which means that even a larger number of patients will need to be screened to detect diabetic retinopathy. The purpose of this study was to describe the experiences of screening for diabetes retinopathy at an ophtalmology department. The pilotstudy was developed by a qualitative inductive approach and data were collected through semi-structured interviews. The material was processed by qualitative content analysis. The main categories that emerged were: security, the importance of information, the importance of accessibility, concerns about the result and its consequences and uncomfortable and time-consuming. The result showed that screening for diabetes retinopathy was important for the informants. It was a security to check their eyes to detect complications in time. It was revealed that they felt a concern for complications due to diabetic retinopathy and what effect this would have on their lives. The informants wanted to get a clearer result of the examination and that the availability would improve. Further nursing research about information, knowledge and increased availability in screening for diabetes retinopathy is needed. Such research would be helpful to improve care patients with diabetes, and to find strategies for reaching out to those who fail to attend screening for diabetes retinopathy.

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.

[Truncated abstract] One of the barriers to understanding and preventing proliferative diabetic retinopathy in humans has been the lack of an appropriate animal model. Historically dog, rat and mouse models of diabetic retinopathy have been studied but none of these exhibit the later changes of proliferative diabetic retinopathy. Animals can be rendered diabetic by surgical pancreatectomy or the use of chemicals such as allozan or streptozotocin or by feeding of a high galactose diet. Alternatively, spontaneous rodent models of diabetes have been examined such as the BB rat, KK mouse or NOD mouse. However, in each case the retinal vascular changes observed are those of early nonproliferative diabetic retinopathy comprising at most saccular microaneurysms, increased thickness of the capillary basement membrane, acellular capillaries and pericyte ghosts. … Fluorecein angiography of this transgenic line clearly demonstrates the presence of leaky new vessels, by the appearance of leakage spots scattered throughout the retina from 1 month of age. These mice constitute a valuable model of diabetic retinopathy. Neovascularization in this animal model is induced by VEGF as in human diabetic retinopathy. The source of VEGF in human diabetic retinopathy is the ischemic inner retina. In this transgenic model the source of VEGF are the photoreceptor cells, which are situated just underneath the inner retina. The neovascularization is not dependent on a particular developmental stage and there is no spontaneous regression of new vessels. Thus any results generated in this model are highly relevant to human diabetic retinopathy.