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Diabetes mellitus currently affects over 422 million people globally and over 80% of patients with diabetes will develop diabetic retinopathy. Patients with diabetic retinopathy initially develop background retinopathy, which does not cause significant deterioration of visual function; however, background retinopathy may progress and lead to proliferative diabetic retinopathy and diabetic macular oedema, both of which cause severe visual dysfunction if left untreated. Current therapies for diabetic retinopathy include invasive intravitreal injections and laser photocoagulation; however these treatments only attenuate the progression of proliferative diabetic retinopathy and diabetic macular oedema. Aside from prevention by maintaining good blood glucose and blood pressure control, there are currently no treatments to prevent progression to late-stage diabetic retinopathy and new innovations in the field have not significantly progressed. For this reason, we have used untargeted –omics approaches to identify previously unknown pathological pathways in diabetes. In this thesis, I have analysed a range of trace metals in donor retinas and found that total copper was increased in diabetic retinas compared with non-diabetic. This result was replicated in streptozotocin-induced diabetic rat retinas and further evidenced by upregulation of metallothioneins and caeruloplasmin in diabetic rat retinas compared with non-diabetic. Treatment with the copper chelator triethylenetetramine modulated these changes, the downstream effects of which require further study. This is the first description, to our knowledge, of dysregulated copper homeostasis in the diabetic retina. I have also mapped metabolic changes in streptozotocin-induced diabetic rat retinas and found previously undescribed metabolite changes such as diabetes-induced downregulation of scyllo inositol. This coincided with substantial changes to retinal lipids during diabetes and changes to individual lipids were consistent within their respective class. I have also found a pattern whereby regardless of the extent of change to a lipid class in diabetes, lipids containing docosahexaenoic acid (22:6 carbon chain) were consistently downregulated. This is thought to be the first study to describe this range of metabolite changes in the diabetic retina but also the first study to describe this range of metabolite analysis concomitantly within the same tissue sample. The data from this study provides new insights into metallomic and metabolic dysfunction in diabetic retinopathy and shown that these data are reproducible. We suggest that there is plenty of scope for further research to investigate mechanisms behind copper dysregulation, how this affects pathogenesis of diabetic retinopathy along with new insights into dysregulated metabolic pathways.

A non-experimental quantitative, descriptive and contextual study which sought to examine the level of awareness about Diabetic Retinopathy (DR), and how aware female diabetic patients were about retinal screening as a preventative measure to eye complications and blindness was conducted. The objective of the study was to explore and describe the variables related to the awareness level of female diabetic patients about Diabetic Retinopathy and diabetic retinal screening. A convenient sample of 149 respondents was obtained. A questionnaire was used to collect data. Data was analysed using the Statistical Package for Social Sciences (SPSS), 13.0 computer software program. Results evidenced a good level of awareness about DR. Recommendations based on the findings were made for consideration in clinical practice, education and research. / Health Studies / M.P.H.

Background: Optical coherence tomography (OCT), multifocal electroretinography (mfERG) and full-field electroretinography (ffERG) give important information about retinal structure and function. Purpose: To collect normative data of macular Cirrus Spectral domain (SD)-OCT assessments and of mfERG measurements of healthy children (papers I and II). To assess the macular thickness with Cirrus SD-OCT and the retinal function with ffERG in 6.5-year-old children born extremely preterm and in children born at term (papers III and IV). Methods: Study participants aged 5-15 years and living in Uppsala County were randomly chosen from the Swedish Birth Register (papers I and II). In papers III and IV, the study participants consisted of children born extremely preterm and children born at term – all were aged 6.5 years. In paper III, the children were living in Stockholm and Uppsala health care regions and, in paper IV, in Uppsala health care region only. Macular thickness was assessed with Cirrus SD-OCT and macular function with mfERG, using the Espion Multifocal system and DTL-electrodes. The retinal function was assessed with ffERG and DTL-electrodes, using the Espion Ganzfield system. Results: Altogether, 58 children participated in paper I and 49 children in paper II. In paper I, the repeatability and reproducibility of the OCT assessments were good. In paper II, the results of the mfERG measurements were in accordance with retinal cone density and there were no significant differences between the right and left eyes. In paper III, 134 preterm children and 145 children born at term constituted the study population. The central macular thickness was significantly thicker in the preterm group than in the control group. Within the preterm group, gestational age (GA), former retinopathy of prematurity (ROP) and male gender were all important risk factors for an increased macular thickness. In paper IV, 52 preterm children and 45 control children constituted the study population. Significantly lower amplitudes and prolonged implicit times of the combined rod and cone responses, as well as of the isolated cone responses, were found in the preterm group when compared with the control group. In paper IV, there was no association between GA, ROP or male gender and the ffERG assessments. Conclusion: Normative data of Cirrus SD-OCT and mfERG assessments were reported. The results of the assessments were reliable. Children aged 6.5 years, born extremely preterm, had a significantly thicker central macula and both rod and cone function were significantly reduced in comparison to children born at term. ROP had an influence on retinal structure but not retinal function in the present cohorts. Our results suggest that retinal development is abnormal in children born extremely preterm. Long-term follow-up studies are necessary in order to evaluate the functional ophthalmological outcome in this vulnerable population of children growing up today.

Bakgrund: Diabetesretinopati är den vanligaste ögonsjukdomen hos personer med diabetes och är en ledande orsak till synnedsättning och blindhet världen över. Patienter som har diabetesretinopati kan vara symptomfria och patienten märker inte att han/hon är drabbad. Det är därför viktigt att patienter som har diabetes screenas regelbundet för att synhotande diabetesretinopati ska upptäckas i ett tidigt stadium så att rätt behandling kan sättas in för att undvika synnedsättning. Syfte: Syftet med studien var att belysa ögonsjuksköterskans uppfattning av olika faktorer som påverkar diabetespatientens följsamhet till ögonbottenfotografering. Metod: En kvalitativ metod med en fenomenografisk ansats användes i studien. Studien har genomförts genom åtta intervjuer med ögonsjuksköterskor på två olika ögonmottagningar i södra Sverige. Resultat: Dataanalysen mynnade ut i fyra olika beskrivningskategorier: Patientens förståelse för sjukdomen, Patientens hälsa och syn, Ögonsjuksköterskans tid med patienten samt Generella hinder. Slutsats: Under studien framkom flera olika faktorer som påverkade patienten att delta eller inte delta vid ögonbottenfotografering. Utifrån resultatet i denna studie drog vi slutsatsen att en ögonsjuksköterska framförallt behöver mer tid tillsammans med varje enskild patient för att kunna informera patienten om diabetes och diabetesretinopati samt motivera till deltagande vid regelbunden ögonbottenscreening. / Background: Diabetic retinopathy is the most common eye disease among people with diabetes and it is a leading cause for sight impairment and blindness all over the world. Patients with diabetic retinopathy can be asymptomatic and the patient can´t tell that he/she is affected. Because of this, it is important that patients with diabetes regularly are screened so that sight threatening retinopathy can be detected in an early state so the proper treatment can be inserted to prevent a sight impairment. Aim: The aim of the study was to illuminate the ophthalmic nurse’s perception of different factors influencing the diabetic patient´s compliance to fundus photography. Method: A qualitative method with a phenomenographic onset has been used in the study. The study has been conducted through eight interviews with ophthalmic nurses working in two different eye clinics in the south of Sweden. Results: The data analysis resulted in four different categories: The patient´s understanding of the disease, The patient´s health and vision, The ophthalmic nurse´s time with the patient and General obstacles. Conclusion: During the study several different factors which influenced the patient to participate or not to participate in fundus photography were found. Based on the result of this study we concluded that an ophthalmic nurse especially needs more time with each patient to be able to inform the patient about diabetes and diabetic retinopathy and to motivate the patient to participate in regular diabetic retinopathy screening.

Objetivo: Avaliação funcional (acuidade visual e sensibilidade ao contraste) e morfológica da retina de pacientes com edema macular diabético (EMD) tratados com bevacizumabe intravítreo e controle glicêmico optimizado durante 24 semanas de acompanhamento. Projeto: Estudo prospectivo intervencionista, randomizado e controlado. Métodos: Quarenta e um olhos de 34 pacientes com diabetes mellitus tipo 2 e EMD com Hemoglobina glicada (HbA1c) <= 11% receberam injeções de bevacizumabe intravítreo (BIV) com controle glicêmico optimizado nas semanas 0, 6, 12 e 18 (grupo 1; n=21); ou receberam simulação de BIV com controle glicêmico optimizado na semana 0 e 6 e, posteriormente, BIV com controle glicêmico optimizado na semana 12 e 18 (Grupo 2; n=20). Mudanças na sensibilidade ao contraste (SC), na acuidade visual (AV) e na espessura foveal (EF) medida por Tomografia de coerência óptica (TCO) foram comparadas antes do início do tratamento e nas semanas 2, 6, 12, 14, 18 e 24. A análise laboratorial do controle sistêmico foi comparada também no início e nas semanas 12 e 24. Resultados: O estudo mostrou AV e EF significativamente melhores em 24 semanas em ambos os grupos. Na 24ª semana, a média da SC melhorou no grupo 1 de 1,14±0,36logCS para 1,33±0,24logCS (P=0,002) e, também, no grupo 2 de 1,11±0,29 para 1,26±0,23logCS (P = 0,004) em 24 semanas, sem diferença significativa entre eles (P = 0,52). Houve uma redução média de 0,78% nos níveis de HbA1c (8,28±1,29% para 7,5±1,20%; P < 0,001) em 24 semanas. As maiores diferenças entre os grupos foram detectadas entre o pré-tratamento e a segunda semana, onde a EF diminuiu rapidamente no grupo 1 em comparação ao grupo 2 (116±115 vs. 17±71?m, respectivamente; P < 0,01). Em 12 semanas, as medidas já não foram estatisticamente significativas (variação da EF = grupo 1 91±184?m vs. grupo 2 62±152?m; P = 0.72). No pré-tratamento, houve correlação significativa entre SC e AV (r = -0,70; P < 0,001) e também entre SC e EF (r = -0,63; P < 0,001) que se manteve em 24 semanas. Conclusão: O uso do bevacizumabe intravítreo associado ao controle glicêmico optimizado melhorou significativamente a função visual, incluindo a sensibilidade ao contraste dos olhos com EMD. No entanto, o controle glicêmico optimizado isolado também se mostrou eficiente durante 12 semanas / Purpose: Functional (visual acuity and contrast sensitivity) and morphological evaluation of the retina of patients with diabetic macular edema (DME) treated with intravitreal bevacizumab and optimized glycemic control on 24-week followup. Project: Prospective, interventional, randomized controlled trial. Methods: Forty-one eyes of 34 patients with type 2 diabetes mellitus and DME with hemoglobin A1c (HbA1c) <= 11% received injections of intravitreal bevacizumab (IVB) with optimized glycemic control (group 1; n=21) at week 0, 6, 12 and 18; or received IVB simulation with optimized glycemic control at week 0 and 6 and, after three months, IVB with optimized glycemic control at week 12 and 18 (Group 2; n=20). Mean Change in contrast sensitivity (CS), best corrected visual acuity (BCVA) and central foveal thickness (CFT) - as measured by optical coherence tomography (OCT) were compared at baseline, and at weeks 2, 6, 12, 14, 18 and 24. A laboratory analysis of systemic control was also compared at baseline and at weeks 12 and 24. Results: The study showed that BCVA and CFT were significantly better in both groups at 24 weeks. Mean CS also improved significantly in group 1 from 1.14±0.36 to 1.33±0,24logCS (P=0,002) and also in group 2 from 1.11±0.29 to 1.26±0.23logCS (P=0,004) at 24 weeks, with no significant difference between them (P = 0.52). There was a mean reduction of 0.78% in HbA1c levels (8,28±1,29 to 7,5±1,20%; P < 0,001) at 24 weeks. The major differences between both groups were detected between the baseline and the second week, whem CFT promptly decreased in group 1 compared to group 2 (116±115 ?m vs. 17±71 ?m; P < 0,01). At 12 weeks, the measures were no longer statistically significant (variation of CFT = group 1 91±184 ?m vs. group 62±152 ?m, P = 0.72). At baseline, there was meaningful correlation between CS and BCVA (r = -0,70; P < 0,001) and also between CS and CFT (r = -0.63; P < 0.001) that remained at 24 weeks. Conclusion: The use of intravitreal bevacizumabe associated with optimized glycemic control improved significantly the visual function, including contrast sensitivity in eyes with DME. However, optimized glycemic control alone also shown to be efficient at 12 weeks

La rétinopathie diabétique (RD) se compose d’une part d’une ischémie rétinienne périphérique et d’autre part d’une exsudation rétinienne responsable d’un œdème maculaire diabétique, première cause de cécité chez les moins 55 ans. Les traitements utilisés actuellement sont non spécifiques et traitent les complications tardives de la RD. Les phases précoces de la RD ne sont donc pas ciblées. L’hyperglycémie chronique entraine un stress oxydant et une activation des PKC qui participent à l’altération des BHR. L’objectif de ce travail a été 1°) d’étudier l’implication de la PKCζ et de la voie Rho/ROCK/Myosine II sur la physiopathogénie de la RD et 2°) de montrer l’effet bénéfique de leurs inhibiteur sur les BHR et sur la reperfusion des capillaires rétiniens. Nous avons confirmé l’hyperactivation de la PKCζ et de la voie Rho/ROCK/Myosine II chez les rats diabétiques et leur participation à la rupture de la BHR externe. Le traitement par leurs inhibiteurs respectifs normalise l’activation des deux enzymes et restaure l’intégrité anatomique et fonctionnelle de la BHR externe. De plus l'hyperactivation de ROCK altère la perfusion rétinienne par 1) constriction focale artériolaire, 2) protrusions membranaires endoluminales des cellules endothéliales (blebbing) et 3) vasoconstriction capillaire diffuse. Nous avons montré que l'ensemble de ces phénomènes étaient réversibles par traitement intravitréen de son inhibiteur le Fasudil. De manière importante le traitement par Fasudil induit également une diminution du VEGF rétinien responsable de la perméabilité des barrières et témoin indirect de l’ischémie rétinienne. Ces travaux éclairent la physiopathogénie de la RD et ouvre des perspectives thérapeutiques permettant de cibler les événements précoces de la RD. / Diabetic retinopathy (DR) mainly results from peripheral retinal ischemia and exudation leading to sight threatening complications such as retinal neovascularization or macular edema. This latter represents the main cause of visual loss among working age individuals. Current treatments address late complications of DR and are non-specific. Therefore, early events are currently not addressed. Chronic hyperglycemia increases oxidative stress and activates PKC leading to blood retinal barrier (BRB) breakdown. The aims of the present work were two fold. First, to assess the implication of PKCζ and the Rho/ROCK/Myosin II pathway on the pathogenesis of DR and second, to assess whether their specific inhibitors have the potential to restore the phenotype. Herein we have demonstrated the pathogenic role of PCKζ and ROCK hyperactivation on the development of diabetes induced external BRB breakdown. Furthermore their inhibitors restored the morphologic and functional aspect of the external BRB. We also found that ROCK hyperactivation was responsible for altered retinal perfusion through several mechanism namely 1) focal constriction of retinal arterioles; 2) endoluminal protrusions of the endothelial cell membrane (blebs) and 3) capillary diffuse vasoconstriction. We were able to demonstrate that all this aspects were reversible by Fasudil, a ROCK inhibitor, administrated into the vitreous. Of importance this treatment decreased also retinal VEGF that is a well-known factor responsible for barrier breakdown and a surrogate marker for retinal ischemia. To conclude the present findings not only shed light on the mechanisms of DR but also open new therapeutic avenues addressing the early events of DR a current unmet medical need.

Diabetic retinopathy is an ischemic retinal neovascular disease causing vision loss among adults. The studies presented involve the design and testing of a gene therapy vector to inhibit retinal revascularization, similar to that found in diabetic retinopathy. Gene therapy has proven to be an effective method to introduce therapeutic proteins to treat retinal diseases. Targeting a specific cell type and expression of therapeutic proteins according to the tissue microenvironment should have an advantage over traditional gene therapy by avoiding unwanted transgene expression. Hypoxia plays a significant role in the pathophysiology of many retinal ischemic diseases. Retinal Mèuller cells provide structural and functional support to retinal neurons, as well as playing a significant role in retinal neovascularization. Targeting Mèuller cells may be an effective strategy to prevent retinal neovascularization under pathological conditions. ... The hypoxia regulated, glial specific vector successfully reduced the abnormal neovascularization in the periphery by 93% and reduced the central vasobliterated area by 90%. A substantial amount of exogenous endostatin was produced in the retinas of P17 OIR mice. A significant increase in human endostatin protein and reduced vascular endothelial growth factor (VEGF) were identified by Western blot and ELISA, respectively. These findings suggest hypoxia-regulated, glial cell-specific scAAV mediated gene expression may be useful to prevent blindness found in devastating retinal diseases involving neovascularization. / by Manas Ranjan Biswal. / Thesis (Ph.D.)--Florida Atlantic University, 2012. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

Alterações macro e microvasculares ocorrem no Diabetes Mellitus (DM). A Retinopatia Diabética (RD) é uma complicação bem prevalente do DM e resulta de microangiopatia generalizada no tecido retiniano que, em diferentes estágios da doença, se observa como edema local, exsudatos, formação de neovasos e hemorragias, sendo a principal causa de cegueira na faixa etária de 20 a 74 anos. Alguns fatores angiogênicos são apontados como possíveis mediadores no desenvolvimento das alterações microvasculares no DM. Dentre eles, a Eritropoietina (EPO), hormônio glicoproteico, possui expressão mediada por alelos específicos do gene EPO. Determinados perfis genéticos para três SNPs-single nucleotide polymorphisms do gene EPO (rs1617640, rs507392, rs551238) encontram-se associados com maiores concentrações de EPO no humor vítreo de pacientes diabéticos com RD, o que pode ser indicativo da relação entre determinado genótipo de risco (TTA) e o desenvolvimento de tal comorbidade. O presente trabalho pretendeu investigar a associação entre o genótipo considerado de risco para o desenvolvimento de RD e alterações funcionais na visão de cores de pessoas com diagnóstico de DM. Tal estudo contou com uma amostra de 95 diabéticos (49 mulheres e 46 homens, média de idade: 48,33 anos; DP: 16,90), com um total de 31 DM tipo 1 e 64 tipo 2 e 114 controles (73 mulheres e 41 homens, média de idade: 38,38 anos; DP: 12,81). Foi realizada avaliação através de teste psicofísico (Cambridge Colour Test CCT), que visou medir o limiar de discriminação nos três eixos de confusão de cores e sequenciamento genético, a partir de amostras de sangue. Para os diabéticos, no eixo de confusão protan, os resultados mostraram uma piora de desempenho para o genótipo TTA/GCC (p= 0,048), com relação aos controles. No eixo de confusão deutan, não houve diferença para qualquer dos genótipos (p= 0,0207), enquanto que para o eixo tritan, o genótipo TTA/GCC esteve associado a uma piora de desempenho (p=0,014). Para os controles, não houve diferença entre os genótipos. Assim, os resultados mostraram uma piora na visão de cores de pacientes DM, associada ao haplótipo TTA/GCC / Diabetic Retinopathy (DR), a prevalent complication of diabetes, is the leading cause of blindness among those aged 20-74 years. Micro and macrovascular changes occur in Diabetes Mellitus (DM) with DR being the most common among these vascular complications, resulting in generalized retinal microgangiopathy. At different stages of the disease, localized edema, exudates and hemorrhages occur. Several pro-angiogenic factors have been suggested as possible mediators in the development of these microvascular changes. Among them is erythropoietin (EPO), a glycoprotein hormone whose expression is mediated by specific alleles of the EPO gene. Specific genetic profiles for three single nucleotide polymorphisms (SNPs) in the EPO gene (rs1617640, rs507392, rs551238) are associated with larger EPO concentrations in the vitreous humor of diabetic patients with RD. This association indicates a possible relationship between the identified genotypes (TTA) and the comorbidity´s development. This work aimed to investigate the association between genotypes considered at risk for the development of DR and functional changes in color vision among individuals diagnosed with DM. Thus, this study included a sample of 95 diabetic patients (49 women and 46 men, average age: 48.33 years; SD: 16.90), with a total of 31 DM type 1 and 64 type 2 and 114 controls (73 women and 41 men, average age: 38.38 years; SD: 12.81). Evaluation was performed using a psychophysical test (Cambridge Colour Test -CCT), to measure the discrimination threshold in three-color confusion axes in addition to genetic sequencing. In the protan axis of confusion color, performance among diabetics with the TTA/GCC genotype was significantly lower (p=0.048) than those in the control group. The results showed a poorer performance among those with the TTA / GCC genotype (p = 0.048), compared to controls. In deutan axis confusion, there was no difference among any of the genotypes (p = 0.0207), while for the tritan axis, the TTA / GCC genotype was associated with a poorer performance (p = 0.014). For the controls, there was no difference between genotypes. Thus, the results showed a worsening in color vision among DM patients associated with TTA / GCC haplotype

O objetivo geral deste estudo foi investigar o efeito do leite humano na redução de respostas biocomportamentais de dor em RNPTs submetidos ao exame de fundo de olho para diagnóstico precoce da retinopatia da prematuridade, em comparação com a sacarose 25%. Trata-se de ensaio clínico randomizado, realizado na unidade neonatal de um hospital universitário de Ribeirão Preto-SP, com 48 prematuros distribuídos randomicamente em dois grupos: leite humano e sacarose, administrados por via oral 2 minutos antes do procedimento doloroso. As variáveis dimensionadas foram mímica facial da escala de dor NFCS, choro, frequência cardíaca e cortisol salivar. A coleta de dados foi realizada em cinco períodos para a mímica facial e o NFCS: basal (05 minutos), olho direito e olho esquerdo, recuperação imediata (05 minutos após o procedimento) e recuperação tardia (05 minutos após a recuperação imediata); quatro períodos para a frequência cardíaca e o choro: basal (05 minutos), procedimento, recuperação imediata e tardia. O cortisol salivar foi coletado antes do início do exame de fundo de olho (basal), após 30 (cortisol resposta) e 60 (cortisol recuperação) minutos do término do exame. O projeto foi aprovado pelo Comitê de Ética em Pesquisa da instituição e foi registrado no Australian and New Zeland Clinical Trials. O Teste de Kolmogorov-Smirnov e o Teste t-student mostraram que os grupos são comparáveis. Para análise das variáveis de desfecho, utilizou-se a Análise de Variância com Medidas Repetidas (RM-ANOVA). Após testar a homogeneidade das variáveis (teste de Levene), foi avaliado o pressuposto da esfericidade das matrizes de variância (teste de Mauchly). Assumindo-se a esfericidade, adotaram-se a análise multivariada, com valor de épsilon < 0,75, e a estatística de Wilk´s Lambda. Para valores de épsilon > 0,75, adotaram-se a análise univariada e a estatística de Hunh-Feldt (HF) ou Greenhouse-Geisser. Para as variáveis categóricas, foi utilizado o teste Qui-quadrado ou Teste exato Fisher. O efeito do leite humano no alívio da dor, decorrente do exame de fundo de olho, não diferiu estatisticamente da sacarose 25%, ao avaliarmos a duração da presença de fronte saliente [Wilk\'s Lamba=0,918, F=0,960, p=0,241], do sulco nasolabial [Wilk\'s Lambda=0,883; F=1,43; p=0,241] e do choro [Wilk\'s Lambda=0,964; F=3,44; p=0,656], e o escore médio do NFCS adaptado ao considerarmos essas duas ações da mímica facial [Wilk\'s Lambda=0,924; F=0,884; p=0,481], a FC [Wilk\'s Lambda=0,977; F=3,44; p=0,792] e a concentração de cortisol salivar [Wilk\'s Lambda=0,978; F=2,45; p=0,612]. A comparação intrasujeitos mostrou diferença significativa nos períodos de coleta dos dados, com aumento nos escores do NFCS, na duração da fronte saliente e do sulco nasolabial, durante o exame do fundo de olho direito e esquerdo, como também no aumento do choro, durante o procedimento doloroso, em comparação com os períodos basal, recuperação inicial e tardia. A concentração do cortisol salivar aumentou significativamente aos 30 e 60 minutos após o procedimento, em comparação com os valores do cortisol basal; não houve diferença entre o cortisol resposta (30 minutos) e recuperação (60 minutos). A duração do sulco nasolabial, do choro e os escores do NFCS no basal não diferiram significativamente dos valores encontrados na recuperação inicial e tardia. Na FC, houve diferença no basal em relação à recuperação imediata, e na duração da fronte saliente houve diferença nas duas recuperações. Concluímos que o efeito do leite humano, na redução das respostas biocomportamentais de dor em prematuros submetidos ao exame de fundo de olho para diagnóstico da retinopatia da prematuridade, não é superior ao efeito obtido com a sacarose 25%, rejeitando-se a hipótese alternativa. / The general aim of this study was to investigate the effect of human milk on reducing biobehavioral pain responses in PN\'s undergoing the ocular fundus examination for the early diagnosis of retinopathy of prematurity, compared with 25% sucrose. This is a randomized clinical trial conducted in the neonatal unit of a university hospital of Ribeirão Preto-SP, with 48 premature newborns randomly distributed into two groups: human milk and sucrose, orally administered 2 minutes before the painful procedure. The variables investigated were the facial movements of the NFCS pain scale, crying, heart rate (HR) and salivary cortisol levels. Data collection was conducted in five periods for the facial movements and NFCS: baseline (05 minutes), right eye and left eye, immediate recovery (05 minutes after the procedure) and delayed recovery (05 minutes after immediate recovery); and in four periods for heart rate and crying: baseline (05 minutes), procedure, immediate and delayed recovery. Salivary cortisol was collected before the start of the fundus examination (baseline), and at 30 minutes (cortisol response) and 60 minutes (cortisol recovery) after the end of the examination. The project was approved by the Research Ethics Committee and was registered in the Australian and New Zealand Clinical Trials. The Kolmogorov-Smirnov test and Student\'s t-test showed that the groups were comparable. For the analysis of the outcome variables, the Analysis of Variance with Repeated Measures (RM-ANOVA) was used. After testing the homogeneity of the variables (Levene\'s test) the assumption of sphericity of the variance matrices was evaluated (Mauchly\'s test). Assuming sphericity, multivariate analysis was adopted, with a < 0.75 value of epsilon and Wilk\'s Lambda statistic. For values of epsilon > 0.75, univariate analysis and the Hunh-Feldt (HF) or Greenhouse-Geisser statistic were adopted. For the categorical variables, the chi-square test or Fisher exact test was used. The effect of human milk on pain relief, arising from the ocular fundus examination, did not differ statistically from 25% sucrose, when the duration of the presence of brow lowering [Wilk\'s Lambda=0.918; F=0.960; p=0.241], of deepening of the naso-labial furrow [Wilk\'s Lambda=0.883; F=1.43; p=0.241] and of crying [Wilk\'s Lambda=0.964; F=3.44; p=0.656] were evaluated, as well as the mean score of the NFCS adapted to consider these two facial movement actions [Wilk\'s Lambda=0.924; F=0.884; p=0.481], the HR [Wilk\'s Lambda=0.977; F=3.44; p=0.792] and the salivary cortisol concentration [Wilk\'s Lambda=0.978; F=2.45; p=0.612]. The intra-subject comparison showed a significant difference in the data collection periods, with an increase in the NFCS scores, in the duration of brow lowering and naso-labial furrow deepening, during the examination fundus of the right and left eyes, as well as increased crying during the painful procedure, compared with the baseline period, immediate and delayed recovery. The concentration of salivary cortisol increased significantly at 30 and 60 minutes after the procedure, compared with the baseline cortisol values; there was no difference between cortisol response (30 minutes) and recovery (60 minutes). The duration of naso-labial furrow deepening, of crying and the NFCS scores at the baseline did not differ significantly from the values found in the immediate and delayed recovery. In the HR, there was no difference between the baseline and the immediate recovery, and in the duration of brow lowering there was no difference in the two recoveries. We conclude that the effect of human milk, on the reduction of biobehavioral responses to pain in preterm infants undergoing the ocular fundus examination for the diagnosis of retinopathy of prematurity, is not greater than the effect obtained with 25% sucrose, rejecting the alternative hypothesis.