Proteomics is the global study of proteins in an organism or a tissue/fluid and is clinically relevant since most disease states are accompanied by specific alterations in an organism's proteome. This review focuses on the application of proteomics to neonatology with particular emphasis on retinopathy of prematurity (ROP), which is a disease in which oxidative stress plays a key pathophysiological role. Oxidative stress is a physiologically relevant redox imbalance caused by an excess of reactive oxygen (ROS) or reactive nitrogen oxide species (RNOS). A major conclusion of this review is that proteomics may be the optimal technology for studying neonatal diseases such as ROP, particularly in the setting of a neonatal intensive care unit (NICU). Proteomics has already identified a number of ROP serum biomarkers. This review will also suggest novel therapeutic approaches to ROP and other neonatal oxidative stress diseases (NOSDs) based on a systems medicine approach.

Patient nonadherence to physicians' prescribed therapeutic regimen is the greatest challenge in the effective treatment of patients with diabetes worldwide. Scientific evidence has revealed that nonadherence to prescribed medication could result in diabetic complications such as cardiovascular disease, retinopathy, nephropathy, and neuropathic diabetic foot ulcers. The purpose of this study was to explore predictive relationships between levels of adherence to antidiabetic medications, patient HbA1c levels, and diabetic complications among Jamaicans, an understudied population. The research question that guided this study was: Do the patient level of adherence and HbA1c levels have any predictive relationship with the severity of diabetic complications (cardiovascular disease, retinopathy, nephropathy and neuropathic foot ulcer) among Jamaicans after controlling for age and gender? The theory of planned behavior was used to guide the study. Data regarding diabetic complications were collected from 119 records during a cross-sectional review of patient dockets. Level of adherence was determined from an interviewer-administered Morisky 8-item adherence scale. A multiple regression analysis revealed that lower levels of patient adherence to treatment and higher HbA1c levels predicted greater severity of cardiovascular disease (p = .000; p = .000), retinopathy (p = .009; p =.090), nephropathy (p =.007; p =.001) and diabetic neuropathic foot ulcers (p =.027; p =.001). Findings from this study will contribute to the knowledge base on diabetic medication nonadherence and may encourage health care professionals to advocate for better medication adherence strategies among people with diabetes.

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ABSTRACT Effective drug delivery to ocular tissues is an unmet challenge that has significant potential to improve the treatment of ocular diseases. Whether the intended drug delivery target is the anterior or posterior segment, the eye’s efficient natural protection mechanisms prevent effective and sustained drug delivery. Anatomical and physiological barriers including the rapid tear turnover that effectively washes away topically applied drugs, the impermeable characteristics of the cornea, conjunctiva, and sclera, and the tight junctions in the blood-ocular barriers make conventional drug delivery methods ineffective. New materials that are able to overcome these barriers are essential to improving the sustained delivery of ophthalmic therapeutics to the intended targets within the eye. This thesis will explore two polymeric drug delivery systems that have the potential to improve therapeutic delivery to ocular tissues. Chapter 1 will discuss the anatomical and physiological barriers to ophthalmic drug delivery and overview current research in this area. Chapter 2 will discuss the synthesis of N-isopropylacrylamide-based copolymers with adjustable gelation temperatures based on composition and molecular weight. Chapter 3 will discuss further development of these copolymers into an injectable, thermoresponsive, and resorbable polymeric drug delivery system intended for the treatment of diseases in the posterior segment. Chapter 4 will discuss the development of mucoadhesive polymeric micelle nanoparticles based on phenylboronic acid intended for topical administration of ophthalmic therapeutics. Finally, Chapter 5 will provide an overview of potential future work on these materials that could further develop and broaden their therapeutic use. / Thesis / Master of Science in Biomedical Engineering

No description available.

Diabetic Retinopathy (DR) is one of the principal sources of blindness due to diabetes mellitus. It can be identified by lesions of the retina, namely microaneurysms, hemorrhages, and exudates. DR can be effectively prevented or delayed if discovered early enough and well-managed. Prior studies on diabetic retinopathy typically extract features manually but are time-consuming and not accurate. In this research, we propose a research framework using advanced retina image processing, deep learning, and a boosting algorithm for high-performance DR grading. First, we preprocess the retina image datasets to highlight signs of DR, then follow by a convolutional neural network to extract features of retina images, and finally apply a boosting tree algorithm to make a prediction based on extracted features. Experimental results show that our pipeline has excellent performance when grading diabetic retinopathy images, as evidenced by scores for both the Kaggle dataset and the IDRiD dataset. / Master of Science / Diabetes is a disease in which insulin can not work very well, that leads to long-term high blood sugar level. Diabetic Retinopathy (DR), a result of diabetes mellitus, is one of the leading causes of blindness. It can be identified by lesions on the surface of the retina. DR can be effectively prevented or delayed if discovered early enough and well-managed. Prior image processing studies of diabetic retinopathy typically detect features manually, like retinal lesions, but are time-consuming and not accurate. In this research, we propose a framework using advanced retina image processing, deep learning, and a boosting decision tree algorithm for high-performance DR grading. Deep learning is a method that can be used to extract features of the image. A boosting decision tree is a method widely used in classification tasks. We preprocess the retina image datasets to highlight signs of DR, followed by deep learning to extract features of retina images. Then, we apply a boosting decision tree algorithm to make a prediction based on extracted features. The results of experiments show that our pipeline has excellent performance when grading the diabetic retinopathy score for both Kaggle and IDRiD datasets.

Background Modern neonatal care has improved the survival rate of extremely preterm infants. These infants are at high risk of malnutrition and growth failure during 3-4 months of hospital care. The objectives of this study was to investigate nutritional intakes during hospitalization and explore associations between nutritional intakes, postnatal growth and retinopathy of prematurity (ROP). Perioperative nutrition in infants undergoing surgery for patent ductus arteriosus (PDA) was also investigated. Methods This is a population-based study of Swedish extremely preterm infants (<27 weeks) born during 2004-2007 (n=602). Detailed data on nutritional supply and anthropometric measurements during hospitalization were retrospectively retrieved from hospital records. Comprehensive data on cohort characteristics, neonatal morbidity and infant mortality were obtained from the Extremely Preterm Infants in Sweden Study (EXPRESS). Results During the first 70 days of life, intakes of energy, protein and several micronutrients, with the exception of iron and some vitamins, were less than estimated requirements, and infants showed severe postnatal growth failure. Energy and protein intake predicted growth in all anthropometric outcomes even when adjusting for severity of illness, and fat intake was positively associated with head growth. Low folate intake was positively correlated with poor weight and length gain while high iron intake, mainly explained by blood transfusions, was negatively associated with poor length gain. Furthermore, a low energy intake was associated with severe ROP (stage 3-5). An increased energy intake of 10 kcal/kg/d was associated with 24% decrease in severe ROP (p=0.01). During the first month, 99% of the infants were exclusively fed human milk. Infants who underwent surgery for PDA (n=140) were malnourished, with energy and macronutrient intakes below minimum estimated requirements before, during and after surgery. Conclusions The severe postnatal growth failure observed in Swedish extremely preterm infants may be prevented by improved intakes of energy, protein, fat and folate and a reduction of the number of blood transfusions. Human milk is the main enteral food source and analyses of human milk macronutrient contents facilitates individualized fortification. Provision of adequate energy intakes during the first four weeks of life may be an effective way to reduce the risk of severe ROP. Perioperative nutrition in infants undergoing PDA surgery needs to be improved. The study results have important implications for nutritional regimens, postnatal growth and health outcome in this new generation of survivors.

La détérioration de la barrière hémato rétinienne et l'oedème maculaire consécutif est une manifestation cardinale de la rétinopathie diabétique (RD) et la caractéristique clinique la plus étroitement associée à la perte de la vue. Alors que l'oedème maculaire affecte plus de 25% des patients souffrant de diabète, les modalités de traitement actuellement disponibles tels que les corticostéroïdes administrés localement et les thérapies anti-VEGF récemment approuvés présentent plusieurs inconvénients. Bien que le lien entre une rupture de l’unité neuro-vasculaire et la pathogénèse de la RD ait récemment été établi, l’influence de la signalisation neuro-vasculaire sur la vasculopathie oculaire diabetique a jusqu’à présent reçu peu d’attention. Ici, à l’aide d’ètudes humaines et animales, nous fournissons la première preuve du rôle essentiel de la molécule de guidage neuronale classique Sémaphorine 3A dans l’instigation de la perméabilité vasculaire maculaire pathologique dans le diabète de type 1. L’étude de la dynamique d’expression de Sémaphorine 3A révèle que cette dernière est induite dans les phases précoces hyperglycèmiques du diabète dans la rétine neuronale et participe à la rupture initiale de la fonction de barrière endothéliale. En utilisant le modèle de souris streptozotocine pour simuler la rétinopathie diabétique humaine, nous avons démontré par une série d’approches analogue que la neutralisation de Sémaphorine 3A empêche de façon efficace une fuite vasculaire rétinienne. Nos résultats identifient une nouvelle cible thérapeutique pour l’oedème maculaire diabétique en plus de fournir d’autres preuves de communication neuro-vasculaire dans la pathogènese de la RD. / The deterioration of the blood retinal barrier and consequent macular edema is a cardinal manifestation of diabetic retinopathy (DR) and the clinical feature most closely associated with loss of sight. While macular edema affects over 25% of patients suffering from diabetes, currently available treatment modalities such as locally administered corticosteroids and recently approved anti-VEGF therapies, present several drawbacks. Although recent insight on the pathogenesis of DR points to a breakdown in the neurovascular unit, neurovascular cross-talk and its influence on diabetic ocular vasculopathy has thus far received limited attention. Here we provide the first evidence from both human and animal studies for the critical role of the classical neuronal guidance cue Semaphorin3A in instigating pathological macular vascular permeability in type I diabetes. Investigation of the dynamics of expression reveal that Semaphorin3A is induced in the early hyperglycemic phases of diabetes within the neuronal retina and precipitates initial breakdown of endothelial barrier function. Using the streptozotocin mouse model as a proxy for human diabetic retinopathy, we demonstrate by a series of orthogonal approaches (gene silencing or treatment with soluble Neuropilin-1 employed as a Semaphorin3A trap), that neutralization of Semaphorin3A efficiently prevents retinal vascular leakage. Our findings identify a new therapeutic target for DME and provide further evidence for neurovascular cross-talk in pathogenesis of DR.

INTRODUÇÃO: Os relatos de alterações da acuidade visual no pósoperatório são esporádicos e acredita-se que apenas os mais graves estejam descritos na literatura. Trata-se de complicação grave e não existem estudos comparativos de avaliação visual antes e após os procedimentos anestésico-cirúrgicos. OBJETIVOS: Analisar a incidência e os fatores de risco para alterações visuais pós-operatórias em pacientes idosos. MÉTODOS: Após aprovação pela Comissão Institucional de Ética em Pesquisa foram estudados 107 pacientes entre 60 anos e 80 anos submetidos a cirurgias com duração superior a 120 minutos. Pacientes com pontuação inferior a 18 pontos na avaliação cognitiva pelo teste de Mini Mental (MMSE) foram excluídos do estudo e também aqueles candidatos a cirurgia oftalmológica, de coluna, cardiovascular, neurocirurgia, de cabeça e pescoço ou otorrinolaringológica, ou os portadores de distúrbios psiquiátricos ou alterações oftalmológicas significativas. Realizou-se avaliação da acuidade visual no dia anterior à cirurgia e no 3º e 21º dias de pósoperatório, sendo esta última realizada apenas nos pacientes que apresentaram algum tipo de alteração visual no 3º PO. As avaliações da acuidade visual foram realizadas utilizando a tabela de Snellen, tabela de Jaeger, biomicroscopia, tonometria óptica, refração, motilidade ocular e fundoscopia. As variáveis independentes preditoras de risco de alteração visual foram selecionadas pelo modelo de regressão logística múltipla. RESULTADOS: A incidência de alteração visual no 3o PO foi de 19,6% (n=21), dos quais 33% (n=7) persistiram com a alteração visual até o 21o PO. A principal alteração foi encontrada ao exame da tabela de Snellen com redução de 30% (p < 0,05) da acuidade visual no 3o PO. Esta alteração foi acompanhada de aumento da refração e da pressão intraocular. Os pacientes diabéticos tipo II, com aumento da frequência cardíaca após a indução anestésica, redução da saturação de oxigênio ao final da cirurgia e submetidos a cirurgias mais prolongadas apresentaram maior risco de alteração visual pós-operatória. DISCUSSÃO: A avaliação por meio de testes específicos permitiu identificar a incidência de alteração visual pósoperatória em pacientes idosos submetidos a anestesia geral para cirurgias com mais de 120 minutos de duração. Os fatores de risco identificados sugerem que pacientes idosos e diabéticos submetidos a cirurgias prolongadas, com aumento da frequência cardíaca e hipotensão após a indução anestésica, redução da saturação de oxigênio ao final da cirurgia e apresentam maior risco de desenvolvimento de alteração visual pósoperatória. Estudos adicionais sobre as causas e formas de prevenção são desejáveis para a melhor compreensão deste evento adverso / BACKGROUND: Reports of changes in visual acuity in the postoperative period are sporadic and it is believed that only the most serious are described in the literature. It is a serious complication and there are no comparative studies evaluating visual function before and after anestheticsurgical procedures. OBJECTIVES: To analyze the incidence and risk factors for postoperative visual changes in elderly patients. METHODS: After approval by the Institutional Ethics Committee, 107 patients between 60 and 80 years of age and candidates for surgery lasting more than 120 minutes were evaluated. Patients with less than 18 points on the cognitive evaluation by the mini-mental state evaluation (MMSE) were excluded from the study and also those candidates to ophthalmologic, spinal, cardiovascular, neurosurgery, head and neck or otorhinolaryngologic surgery, or those with psychiatric disorders or ophthalmological changes. Visual acuity assessment was performed on the day before surgery and on the 3rd and 21st postoperative days (POD), the latter being performed only in patients who presented some type of visual alteration in the 3rd POD. Visual acuity assessments were performed using the Snellen table, Jaeger table, biomicroscopy, optical tonometry, refraction, ocular motility and fundoscopy. The independent predictors of risk of visual impairment were selected by the multiple logistic regression model. RESULTS: The incidence of visual impairment in the 3rd POD was 19.6% (n = 21), of which 33% (n = 7) persisted with the visual alteration until the 21st POD. The main alteration was found when examining the Snellen chart with a 30% reduction (p < 0.05) in visual acuity in the 3rd POD. This alteration was accompanied by an increase in refraction and intraocular pressure. Type II diabetic patients with increased heart rate after anesthetic induction, reduction of oxygen saturation at the end of surgery, and submitted to more prolonged surgeries presented a greater risk of postoperative visual changes. DISCUSSION: The evaluation through specific tests allowed the identification of the incidence of postoperative visual alteration in elderly patients submitted to general anesthesia for surgeries lasting more than 120 minutes. The risk factors identified suggest that elderly and diabetic patients undergoing prolonged surgeries, with increased heart rate and hypotension after induction, and reduction of oxygen saturation at the end of surgery present a higher risk of developing postoperative visual changes. Additional studies on the causes and forms of prevention are desirable for the better understanding of this adverse event

Ziel dieser Arbeit war es, in Querschnitts- und prospektiven Longitudinalstudien die Diagnostik diabetes-assoziierter Autoimmunerkrankungen (Autoimmun-Thyreoiditis und Zöliakie, primäre Komorbiditäten) sowie diagnostische Verfahren zur Früherkennung von sekundären Spätkomplikationen (Retinopathie und Nephropathie, sekundäre Komorbiditäten) bei Kindern und Jugendlichen mit Typ 1 Diabetes zu evaluieren. Mit Hilfe eines Screenings spezifischer Antikörper (EmA, IgA-Gliadin-, IgA-tTG-Antikörper) konnte eine höhere als bisher berichtete Zöliakie-Prävalenz bei zwei Prozent der asymptomatischen Kinder mit Typ 1 Diabetes festgestellt werden. Eine Autoimmun-Thyreoiditis wurde durch Untersuchungen von Schilddrüsen-spezifischen Antikörpern (Anti-TPO, Anti-TG) bei bis zu 20 Prozent der Kinder und Jugendlichen diagnostiziert. Mädchen hatten signifikant häufiger Schilddrüsen-Antikörper als Jungen. Mit zunehmendem Alter der Patienten stieg die Prävalenz der Antikörper. Die Anwesenheit positiver Schilddrüsen-Antikörper war mit höheren TSH-Werten assoziiert. Sehr hohe Schilddrüsen-Antikörper (Anti-TPO, Anti-TG) waren prädiktiv für die spätere Entwicklung einer subklinischen Hypothyreose. Hinsichtlich der sekundären Komorbiditäten konnte anhand von Messungen der glomerulären (Alb, Tf, IgG) und tubulären Marker (NAG, alpha1-MG) nachgewiesen werden, dass bei Patienten mit Diabetes nicht nur eine glomeruläre, sondern auch eine tubuläre renale Dysfunktion vorliegen kann. Eine erhöhte NAG-Urinausscheidung war prädiktiv für die Entwicklung einer Mikroalbuminurie. Für die Retinopathieentwicklung war die Stoffwechseleinstellung (HbA1c) von wesentlicher Bedeutung, insbesondere während der ersten Diabetesjahre. In der Pubertät kam es zu einer Beschleunigung der Retinopathieentwicklung. Weitere Risikofaktoren für sekundäre Spätkomplikationen insbesondere Retinopathie waren Blutdruck, Lipidstoffwechsel (Triglyzeride, HDL-Cholesterin) und Gesamtrenin. Für die Prognose und Prävention primärer und sekundärer Komorbiditäten bei Kindern mit einem Typ 1 Diabetes als chronische Grunderkrankung ist ein frühzeitiges und regelmäßiges Screening von wesentlicher Bedeutung. / The aim of this study was the evaluation of diagnostic procedures for the early detection of diabetes-associated autoimmune diseases (autoimmune thyroiditis and coeliac disease, primary co-morbidity) as well as of diabetes-specific late complications (retinopathy and nephropathy, secondary co-morbidity) in children and adolescents with type 1 diabetes. The prevalence of coeliac disease among asymptomatic children with type 1 diabetes was 2 percent based on a screening for specific autoantibodies (EMA, IgA-gliadin-, IgA-tTG-antibodies) being higher than reported previously. Autoimmune thyroiditis was diagnosed in up to 20 percent of children and adolescents according to screening procedures for thyroid-specific antibodies (anti-TPO, anti-TG). Girls had more frequently thyroid antibodies than boys. The prevalence of thyroid antibodies increased with increasing age of patients. The presence of thyroid antibodies was associated with higher TSH values, while very high values of thyroid antibodies were predictive for the development of a subclinical hypothyroidism. Studies concerning the prevalence of secondary co-morbidity in young patients with type 1 diabetes revealed that not only glomerular, but also tubular renal dysfunction may occur in these patients. These studies based on the measurement of urinary excretion of glomerular (Alb, Tf, IgG) and tubular (NAG, alpha1-MG) markers. Elevated urinary excretion of NAG was predictive for the development of microalbuminuria. Glycaemic control (HbA1c), particularly during the first years of diabetes, constituted a significant parameter for the development of retinopathy, while puberty may accelerate the development of this late complication. Arterial blood pressure, lipid profile (triglycerides, HDL-cholesterol) and total renin had been found to be additional risk factors for the development of late complications, particularly retinopathy. An early and regularly performed screening is recommended for the prognosis and prevention of primary and secondary co-morbidity in children with type 1 diabetes.