Abstract In this thesis study, the primary structure of the human α1(XVIII) polypeptide was elucidated, its tissue distribution was studied, and the phenotypic changes in the mouse eye due to lack of type XVIII collagen in a knock-out mouse model were studied further. In addition, the consequences of simultaneous lack of both type XVIII and XV collagen were studied in a mouse model lacking both of these proteins. Two variant forms of human α1(XVIII) polypeptide were identified in this study, although, to date, a third form has also been characterized. The analysis of tissue distribution of the two polypeptide forms revealed differences in their tissue distribution, since the longest variant occurs prominently in the liver, while the short form is the major transcript in other tissues studied, e.g. in the kidney. The study of the type XVIII single null mouse eyes revealed abnormalities in the anterior eye segment in addition to the previously reported defects in the posterior eye part. In the type XVIII single null mice the iris was fragmented, pigment deposits could be seen in the pupil, and the pupillary ruff in the edge of a normal mouse iris was missing in these mice. The ciliary body was also abnormal, since the ciliary processes start to show regression in adult animals and eventually the basal infoldings of the non-pigmented ciliary body epithelia become flattened in the null mice. The intraocular pressure stabilizes to a lower level in adult mutant mice compared to controls, most likely reflecting the atrophied ciliary epithelia. The BM zones were also defective in the type XVIII null mouse eyes. The absence of an immunosignal with one of the antibodies detecting laminin γ2 chain in the type XVIII null mouse eyes may implicate conformational changes in the laminin γ2 chain due to lack of type XVIII collagen, and subsequently interaction between type XVIII collagen and laminin γ2 chain in normal mouse eye BMs. The study of the type XVIII and XV double null mice revealed that these mice were viable and fertile and had no major additional abnormalities compared to both single null mice. However, the regression of hyaloid capillaries (vasa hyaloidea propria, VHP) was studied in these mice, and a slight delay in the detachment of these vessels from the retina was noticed. Thus, the two collagens do not function entirely independently from each other. The studies with type XVIII collagen single null mice indicate that in addition to the posterior eye phenotype, this collagen is needed for the normal structural integrity of the anterior eye segment and basement membranes of the eye. The mouse model lacking both type XVIII and type XV collagen indicates that the roles of the two collagens are essentially diverse, although a slight compensatory effect was observed in the detachment of the hyaloid capillaries from the retina.

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Une des applications de l’échographie médicale est celle de l’ophtalmologie qui pose de nombreux problèmes spécifiques liés en partie à la faible dimension de l’oeil et à la précision importante que requièrent les mesures intraoculaires. En effet, avec le développement de la chirurgie réfractive qui regroupe ensemble des techniques capables de corriger les erreurs de réfraction et l’avènement des implants intraoculaires, le chirurgien ophtalmologiste est amené à surveiller la tolérance et les effets secondaires de ces implants sur les structures du segment antérieur. L’échographie à haute fréquence apporte la résolution suffisante pour cette tâche. Cependant, le développement de l’échographie 3D permet une extension des applications ophtalmologiques notamment pour le dimensionnement des implants en préopératoire. La modélisation 3D du segment antérieur permet d’étudier le comportement des implants et surtout de dessiner à terme un implant « sur mesure » pour le patient. C’est dans ce contexte que nous présentons une méthode originale de segmentation et de reconstruction 3D du segment antérieur par échographique haute fréquence en utilisant l’ajustement de modèles 3D. Nous utilisons un système échographique 3D de type main-libre, composé d’une sonde échographique haute fréquence, et d’un module de localisation actif comprenant une caméra et des marqueurs infrarouges. Ce système échographique 3D nous permet d’obtenir des images avec des informations de positionnement dans l’espace tridimensionnel associées. Nous avons ainsi pu mettre en place toute une chaîne d’acquisitions et de traitements des images échographiques. Nous créons, à partir d’images échographiques du segment antérieur oculaire, des modèles de référence 3D réalistes. Nous proposons ainsi une méthode d’ajustement de modèles 3D de référence sur des données 3D échographiques via l’utilisation de l’algorithme de recalage ICP. Nous avons également sélectionné et adapté différentes méthodes pour l’évaluation de l’approche de reconstruction proposée. Ces méthodes permettent de mettre en valeur la précision de ces reconstructions. / Ophthalmology is one of the clinical application fields of ultrasound imaging, for which numerous specific issues arise, related in part to the eye’s small anatomical dimensions combined with the high level of accuracy requirements associated with intraocular measurements. Indeed, since the development of refractive surgery including all the techniques dedicated to the correction of refractive errors, as well as the emergence of intraocular lens (IOL), ophthalmic surgeons have to monitor overall acceptance as well as secondary effects related to these implants on the structures of the anterior eye segment. High frequency ultrasound imaging provides the required spatial resolution for this task. However, the development of 3D ultrasound imaging allows for the development of new applications in ophthalmology, for instance pre-operative dimensioning of the lens. 3D modelling of the anterior eye segment therefore allows studying the IOL behaviour and may help designing future personalized IOL tailored for each patient. Within this context, we present an original 3D segmentation and reconstruction method based on 3D models registration, dedicated to the anterior eye segment acquired in high frequency ultrasound imaging. We used a 3D ultrasound free-hand acquisition system, composed of a high frequency ultrasound probe and a localization module based on a camera and infrared markers. This 3D ultrasound system provides images along with associated 3D spatial positioning information. We were therefore able to develop an entire ultrasound images acquisition and processing chain. This allowed us creating realistic reference 3D models from sequences of ultrasound images of the anterior eye segment. We thus propose a method based on the iterative closest point (ICP) algorithm for the registration of the 3D reference models to 3D ultrasound acquired data. We have also selected and adapted various methods for the evaluation of the proposed reconstruction process. These methods highlight the accuracy of the obtained reconstructions.

INTRODUÇÃO: O glaucoma de ângulo fechado é reconhecido como uma das principais causas de cegueira mundial. A iridotomia representa o tratamento de eleição nos casos com fechamento angular primário, entretanto, este procedimento pode não ser suficiente para proporcionar abertura do ângulo irido-corneano, controle da pressão intra-ocular (PIO) e estabilização do processo da lesão glaucomatosa. O presente estudo tem como objetivo avaliar a morfologia do segmento anterior do olho em uma amostra de pacientes brasileiros, e realizar uma comparação entre olhos normais (sem sinais de fechamento angular prévio) e olhos com ângulos oclusíveis, antes e após a realização da iridotomia. MÉTODOS: Realizou-se um estudo prospectivo observacional tipo caso-controle em pacientes da Clínica Oftalmológica do HC - FMUSP, onde 40 olhos com ângulos oclusíveis (grupo caso) e 27 olhos normais (grupo controle) foram examinados durante o período de agosto de 2003 a dezembro de 2004. Os pacientes do grupo controle foram pareados por idade, sexo e raça. Os exames de gonioscopia e biometria ultra-sônica foram utilizados para comparar os 27 olhos normais com os 40 olhos com ângulos oclusíveis, antes e após a realização da iridotomia. A biometria ultra-sônica mediu o comprimento axial do olho (CAX), a profundidade da câmara anterior (PCA) e o diâmetro ântero-posterior do cristalino (DAPC). Os 27 olhos do grupo controle foram comparados, através da biomicroscopia ultra-sônica, antes e após a iridotomia com os 31 olhos do grupo caso, que não apresentavam goniosinéquias no quadrante inferior. As imagens da UBM foram obtidas em cortes radiais sobre típicos processos ciliares, no claro e no escuro. A distância da abertura angular a 500?m do esporão escleral (DAA500), profundidade da câmara anterior (PCA-UBM), distância do trabeculado aos processos ciliares (DTPC), espessura da íris a 500?m do esporão escleral (EI500) e distância do esporão escleral à inserção da íris (linha X) foram medidas nas imagens da UBM obtidas às 6 horas. As freqüências de processos ciliares longos sem sulco ciliar e fechamento angular aposicional no escuro também foram determinadas nessas imagens. RESULTADOS: Os parâmetros morfológicos dos 27 olhos do grupo controle apresentaram diferenças significativas quando comparados com os 40 olhos do grupo caso. Os olhos normais apresentaram ângulo irido-corneano mais aberto, menor DAPC e maiores CAX e PCA. Nas imagens da UBM os 27 olhos normais apresentaram maior DAA500, PCA-UBM, linha X, e também, maior DTPC que os 31 olhos com ângulos oclusíveis (651 ± 119 ?m e 508 ± 116 ?m; p < 0.001); porém, a EI500 não apresentou diferença significativa entre os dois grupos. Após a realização da iridotomia foi observado uma abertura significativa do seio camerular, e uma diminuição da freqüência de fechamento angular aposicional nas imagens da UBM obtidas no escuro (28/31 para 16/31). Processos ciliares longos sem sulco ciliar foram observados em 61% (19/31) dos olhos do grupo caso após a iridotomia e em 33% (9/27) dos olhos do grupo controle. CONCLUSÃO: A presença de processos ciliares longos sem sulco ciliar foi um achado comum não somente nos olhos com ângulos oclusíveis como também nos olhos normais. No entanto, nos olhos do grupo caso, os processos ciliares estavam localizados, em média, numa posição mais anterior. Após a iridotomia, mais da metade dos olhos com ângulos oclusíveis continuaram apresentando fechamento angular aposicional na UBM. Os valores preditivos da presença de fechamento angular aposicional (associada ou não a processos ciliares longos sem sulco ciliar) na detecção de pacientes sob risco de apresentarem episódios de fechamento angular precisam ser avaliados em estudos futuros / Introduction: Angle closure glaucoma is emerging as one of the leading cause of worldwide blindness. Laser iridotomy (LI) has been proposed as first line therapy for patients with angle closure, however this procedure may not be effective opening the irido-corneal angle, controlling intra-ocular pressure (IOP) and halting glaucoma progression in all cases. Our study aimed to evaluate anterior segment morphology on a cohort of Brazilian patients comparing normal eyes (no signs of angle closure) to angle closure eyes before and after LI. Methods: In this prospective observational case control study, performed from August of 2003 to December of 2004, we evaluated 40 angle closure eyes and 27 normal control eyes with no signs of angle closure at clinical exam, paired by age, race and gender. We used gonioscopy and A-scan biometry to compare anterior segment morphology of 27 normal control eyes to 40 angle closure eyes of patients from our service, before and after LI. We also used ultrasound biomicroscopy (UBM) exam, to compare 27 normal control eyes to 31 of 40 angle closure eyes with no goniosynachiae at the inferior quadrant evaluated by gonioscopy, before and after LI. Immersion 50-MHz high-frequency ultrasound transducer was used to obtain UBM images in radial scans through a typical ciliary process, in both standard light and dark conditions. A-scan biometry measured axial length (AXL), anterior chamber depth (ACD) and lens thickness (LENS). The angle opening distance at 500?m from the scleral spur (AOD500), trabecular ciliary process distance (TCPD), iris thickness at 500?m and the distance from scleral spur to iris insertion (line X) were measured at UBM images obtained at the inferior quadrant. The frequency of appositional angle closure and the presence of long ciliary process with no ciliary sulcus were also evaluated at UBM images. Results: At gonioscopy and A-scan biometry exam, 27 normal eyes had a significant wider iridocorneal angle opening, a thinner LENS and a greater AXL, ACD than angle closure eyes. At UBM exam, 27 normal control eyes had an significant wider AOD500, line X and also, a longer TCPD than angle closure eyes (651 ± 119 ?m vs. 508 ± 116 ?m; p < 0.001); however no differences were observed in iris thickness between the two groups. After LI, we observed a significant irido-corneal angle opening and the number of angle closure eyes with UBM appositional angle closure in dark condition decreased from 28/31 to 16/31. A long ciliary processes with no ciliary sulcus were observed in 61% (19/31) of angle closure eyes after LI, and also in 33% (9/27) of normal control eyes. Conclusion: A long ciliary processes and absence of ciliary sulcus were a quite common finding not only in angle closure eyes, but also in normal control eyes. However, ciliary processes were located more anteriorly in angle closure eyes. On this cohort of Brazilian patients, more than half of studied eyes submitted to LI maintained UBM appositional angle closure. Whether this apposition with or without long ciliary process and absence of ciliary sulcus detected at UBM images after LI is associated to further goniosynachiae formation and/or loss of IOP control remains to be evaluated

INTRODUÇÃO: O glaucoma de ângulo fechado é reconhecido como uma das principais causas de cegueira mundial. A iridotomia representa o tratamento de eleição nos casos com fechamento angular primário, entretanto, este procedimento pode não ser suficiente para proporcionar abertura do ângulo irido-corneano, controle da pressão intra-ocular (PIO) e estabilização do processo da lesão glaucomatosa. O presente estudo tem como objetivo avaliar a morfologia do segmento anterior do olho em uma amostra de pacientes brasileiros, e realizar uma comparação entre olhos normais (sem sinais de fechamento angular prévio) e olhos com ângulos oclusíveis, antes e após a realização da iridotomia. MÉTODOS: Realizou-se um estudo prospectivo observacional tipo caso-controle em pacientes da Clínica Oftalmológica do HC - FMUSP, onde 40 olhos com ângulos oclusíveis (grupo caso) e 27 olhos normais (grupo controle) foram examinados durante o período de agosto de 2003 a dezembro de 2004. Os pacientes do grupo controle foram pareados por idade, sexo e raça. Os exames de gonioscopia e biometria ultra-sônica foram utilizados para comparar os 27 olhos normais com os 40 olhos com ângulos oclusíveis, antes e após a realização da iridotomia. A biometria ultra-sônica mediu o comprimento axial do olho (CAX), a profundidade da câmara anterior (PCA) e o diâmetro ântero-posterior do cristalino (DAPC). Os 27 olhos do grupo controle foram comparados, através da biomicroscopia ultra-sônica, antes e após a iridotomia com os 31 olhos do grupo caso, que não apresentavam goniosinéquias no quadrante inferior. As imagens da UBM foram obtidas em cortes radiais sobre típicos processos ciliares, no claro e no escuro. A distância da abertura angular a 500?m do esporão escleral (DAA500), profundidade da câmara anterior (PCA-UBM), distância do trabeculado aos processos ciliares (DTPC), espessura da íris a 500?m do esporão escleral (EI500) e distância do esporão escleral à inserção da íris (linha X) foram medidas nas imagens da UBM obtidas às 6 horas. As freqüências de processos ciliares longos sem sulco ciliar e fechamento angular aposicional no escuro também foram determinadas nessas imagens. RESULTADOS: Os parâmetros morfológicos dos 27 olhos do grupo controle apresentaram diferenças significativas quando comparados com os 40 olhos do grupo caso. Os olhos normais apresentaram ângulo irido-corneano mais aberto, menor DAPC e maiores CAX e PCA. Nas imagens da UBM os 27 olhos normais apresentaram maior DAA500, PCA-UBM, linha X, e também, maior DTPC que os 31 olhos com ângulos oclusíveis (651 ± 119 ?m e 508 ± 116 ?m; p < 0.001); porém, a EI500 não apresentou diferença significativa entre os dois grupos. Após a realização da iridotomia foi observado uma abertura significativa do seio camerular, e uma diminuição da freqüência de fechamento angular aposicional nas imagens da UBM obtidas no escuro (28/31 para 16/31). Processos ciliares longos sem sulco ciliar foram observados em 61% (19/31) dos olhos do grupo caso após a iridotomia e em 33% (9/27) dos olhos do grupo controle. CONCLUSÃO: A presença de processos ciliares longos sem sulco ciliar foi um achado comum não somente nos olhos com ângulos oclusíveis como também nos olhos normais. No entanto, nos olhos do grupo caso, os processos ciliares estavam localizados, em média, numa posição mais anterior. Após a iridotomia, mais da metade dos olhos com ângulos oclusíveis continuaram apresentando fechamento angular aposicional na UBM. Os valores preditivos da presença de fechamento angular aposicional (associada ou não a processos ciliares longos sem sulco ciliar) na detecção de pacientes sob risco de apresentarem episódios de fechamento angular precisam ser avaliados em estudos futuros / Introduction: Angle closure glaucoma is emerging as one of the leading cause of worldwide blindness. Laser iridotomy (LI) has been proposed as first line therapy for patients with angle closure, however this procedure may not be effective opening the irido-corneal angle, controlling intra-ocular pressure (IOP) and halting glaucoma progression in all cases. Our study aimed to evaluate anterior segment morphology on a cohort of Brazilian patients comparing normal eyes (no signs of angle closure) to angle closure eyes before and after LI. Methods: In this prospective observational case control study, performed from August of 2003 to December of 2004, we evaluated 40 angle closure eyes and 27 normal control eyes with no signs of angle closure at clinical exam, paired by age, race and gender. We used gonioscopy and A-scan biometry to compare anterior segment morphology of 27 normal control eyes to 40 angle closure eyes of patients from our service, before and after LI. We also used ultrasound biomicroscopy (UBM) exam, to compare 27 normal control eyes to 31 of 40 angle closure eyes with no goniosynachiae at the inferior quadrant evaluated by gonioscopy, before and after LI. Immersion 50-MHz high-frequency ultrasound transducer was used to obtain UBM images in radial scans through a typical ciliary process, in both standard light and dark conditions. A-scan biometry measured axial length (AXL), anterior chamber depth (ACD) and lens thickness (LENS). The angle opening distance at 500?m from the scleral spur (AOD500), trabecular ciliary process distance (TCPD), iris thickness at 500?m and the distance from scleral spur to iris insertion (line X) were measured at UBM images obtained at the inferior quadrant. The frequency of appositional angle closure and the presence of long ciliary process with no ciliary sulcus were also evaluated at UBM images. Results: At gonioscopy and A-scan biometry exam, 27 normal eyes had a significant wider iridocorneal angle opening, a thinner LENS and a greater AXL, ACD than angle closure eyes. At UBM exam, 27 normal control eyes had an significant wider AOD500, line X and also, a longer TCPD than angle closure eyes (651 ± 119 ?m vs. 508 ± 116 ?m; p < 0.001); however no differences were observed in iris thickness between the two groups. After LI, we observed a significant irido-corneal angle opening and the number of angle closure eyes with UBM appositional angle closure in dark condition decreased from 28/31 to 16/31. A long ciliary processes with no ciliary sulcus were observed in 61% (19/31) of angle closure eyes after LI, and also in 33% (9/27) of normal control eyes. Conclusion: A long ciliary processes and absence of ciliary sulcus were a quite common finding not only in angle closure eyes, but also in normal control eyes. However, ciliary processes were located more anteriorly in angle closure eyes. On this cohort of Brazilian patients, more than half of studied eyes submitted to LI maintained UBM appositional angle closure. Whether this apposition with or without long ciliary process and absence of ciliary sulcus detected at UBM images after LI is associated to further goniosynachiae formation and/or loss of IOP control remains to be evaluated