Thesis (MScMed (Dept. of Biomedical Sciences. Anatomy and Histology) --University of Stellenbosch, 2007. / Thyroid nodules are a common clinical problem encountered by physicians, surgeons and radiologists who deal with the head and neck region. However, most follicular lesions of the thyroid are benign, so that the indications for surgery should be as accurate as possible. The morphological difficulty on fine-needle aspiration biopsy (FNAB) of reliably distinguishing preoperatively between benign and malignant lesions has led to a search for ancillary methods that can assist with the diagnosis. The aim of the first study was to develop a cytological scoring system to improve diagnostic accuracy of fine-needle aspiration biopsy of papillary carcinomas with special reference to the follicular variant of papillary carcinoma. The objective of the second study was the application of immunodiagnostic markers Galectin-3 and HBME-1 to histology tissue sections and their corresponding fine-needle aspiration cytology smears to assess their value in distinguishing benign from malignant thyroid lesions. In the first study 16 different cytological features such as background, architecture and cellular morphology were quantatively assessed and scored. Only 14 of the 16 variables were statistically significant. The statistical analysis demonstrated that a score ≥ 4 was indicative of a papillary carcinoma with a sensitivity of 96%. A score < 4 suggested a benign multinodular goiter with a specificity of 97%. In the second study Galectin-3 and HBME-1 were applied to histology tissue sections and their corresponding fine-needle aspiration cytology smears. Statistical analyses showed that the sensitivity of immunohistochemistry for diagnosing malignancy was better than the immunocytochemistry, but the specificity of immunocytochemistry was superior. Furthermore the diagnostic accuracy of immunohistochemistry (86%) and immunocytochemistry (88%) using co-expression of these two antibodies was excellent. In this study on immunocytochemistry, papillary carcinomas were clearly identified with a 100% co-expression in the classic and 71% in the follicular variant of papillary carcinoma. For the surgeon the identification of papillary carcinoma is critical, as this determines the extent of surgery. Similary, the confirmation of a non-neoplastic lesion may prevent surgery. In most cases follicular neoplasms, benign or malignant, will usually be excised for histopathology, prior to definite therapy. These studies show that the implementation of ancillary methods such as a scoring system and immunodiagnostic markers can improve the diagnostic accuracy of thyroid fine-needle aspiration biopsies in our laboratory. This may lead to better management of thyroid nodules. However, it is advisable that cytopathologists always take all the clinical features and image analyses into consideration before making a diagnosis.

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The early detection of acquired losses of colour vision can provide the ophthalmologist with a very sensitive indicator of visual dysfunction. As a result we have developed and tested an automated, CRT-based, chromatic discrimination system that allows us to measure acquired colour-vision deficits with great precision. This system, known as the Sussex Gratings Machine, can produce chromatic stimuli in any direction in equal luminance colour space. However, we have found that measurements made along a constant MIL-cone axis (Tritan) or a constant S-cone (Red/Green) confusion axis are most useful. Using this system we have investigated acquired colour vision deficits in diabetes ,. and thyroid eye disease. We have shown that tritan discrimination losses can be used to screen for severe diabetic retinopathy and also to predict those who are likely to develop it within 18 months. We have also confirmed that acquired tritan discrimination losses are a very useful indicator of optic-nerve compression in thyroid eye disease.

Effects of sulfadiazine, sulfathiazole, and sulfapyridine on the thyroid gland and blood pressure were investigated in the rat. Thiouracil, a known potent anti-thyroid substance, was employed as a standard with which the drugs were compared. Four groups of young male albino rats were injected with graded doses of thiouracil, sulfadiazine, sulfathiazole, and sulfapyridine, suspended in distilled water, over a '6-dsy period, respectively. A 0.027' solution of the drug was incorporated into the drinking water daily. A control group was injected with physiological saline and a 0.02" solution of the saline solution was incorporated into the drinking water. Thiouracil and the sulfenamiaes acted as anti-thyroid agents. Goiterous conditions developed, including thyroid hypertrophy, reduced food intake, as well as an increase in body weight concomitantly with reduced oxygen consumption and reduction in the level of iodinated compounds in the blood. A slight increase in the systolic blood pressure was also noted. Results were obtained by means of spectrophotometry, oxygen consumption rates, blood pressure determinations, and gross analyses of the thyroid glands.

published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / Surgery / Master / Master of Philosophy

L’hypothyroïdie congénitale (HC) est une maladie relativement fréquente, touchant un nouveau-né sur 3000-4000, et dont la majorité des cas sont causés par un défaut dans le développement embryonnaire de la glande. Il existe plusieurs arguments en faveur d’une cause génétique dans une minorité de ces dysgénésies thyroïdiennes mais, à ce jour, seuls quelques cas ont put être reliés à une mutation dans l’un ou l’autre de trois gènes codant pour des facteurs de transcription impliqués dans le développement de la thyroïde (TITF1, PAX8 et FOXE1). Au cours de notre travail de thèse, nous avons caractérisé la 6ème mutation du gène PAX8 à l’état hétérozygote, dans un cas familial d’HC. Nous avons étudié l’impact fonctionnel de cette altération qui entraîne une perte de liaison de la protéine mutée à une séquence cible spécifique, ainsi qu’une diminution drastique de la synergie de transactivation en association avec Titf1. Le phénotype des patients est également intéressant à plus d’un titre. En effet, nous avons pu observer que les mutations de PAX8 sont compatibles avec le développement d’une thyroïde en place et de taille normale à la naissance, pouvant conduire à un diagnostic erroné de dyshormonogenèse. De plus, un des trois patients présente un phénotype rénal qu’il est tentant de relier à la mutation de PAX8 étant donné que ce gène est exprimé durant le développement de cet organe, tout comme dans la thyroïde. Notre travail a également consisté en l’élaboration d’une librairie SAGE du bourgeon thyroïdien en développement, afin de rechercher de nouveaux gènes candidats impliqués dans le développement de la glande thyroïde. Grâce à une technique d’amplification d’ARN, nous avons obtenu une librairie d’environ 94.000 étiquettes à partir de bourgeons thyroïdiens provenant d’embryons de souris au 11ème jour de développement. Cette librairie nous a permis d’identifier une nouvelle isoforme du transcrit de Titf1 modifiant l’extrémité 3’-non codante du messager, ainsi qu’un gène de fonction inconnue mais dont le profil d’expression ainsi que sa grande conservation au cours de l’évolution laissent suggérer un rôle important, tant dans les tissus embryonnaires que dans les tissus adultes. Ces deux découvertes valident le caractère prédictif de notre librairie qui constitue un outil de choix pour l’identification de nouveaux gènes de développement thyroïdien et donc de nouveaux candidats pour l’étude des mécanismes étiopathogéniques à la base des dysgénésies thyroïdiennes. / Congenital hypothyroidism (CH) is a relatively frequent disease affecting 1 every 3000-4000 newborns. The majority of CH cases are caused by a defect in the embryonic development of the gland. There exists several arguments in favor of a genetic cause for a minority of these thyroid dysgeneses but, to this day, only a few cases have been related to a mutation in one of three genes coding for transcription factors implicated in thyroid development (TITF1, PAX8 and FOXE1). In the course of this work, we have caracterized the 6th mutation of the PAX8 gene, in the heterozygous state, in a familial case of CH. We have studied the functional impact of this modification which leads to a loss of the protein’s DNA-binding properties and to a severe reduction in the transactivation synergy in association with Titf1. The phenotype of the patients presents also interesting features. Indeed we have observed that the PAX8 mutations are compatible with the development of an in-place, normal-sized thyroid at birth, which could lead to an erroneous diagnostic of dyshormonogenesis. Moreover, one of the three patients presents with a renal phenotype (unilateral kidney agenesis) which is tempting to relate to the PAX8 mutation, given this gene is expressed during kidney development. Our work also consisted in the generation of an embryonic thyroid bud SAGE library, which we used to search for new candidate genes implicated in thyroid development. With the help of a RNA amplification technique, we obtained a library of roughly 94.000 tags starting from mous thyroid buds at E11. This library allowed us to identify a new Titf1 splicing variant modifying the 3’-UTR of the transcript, and a gene of unknown function. The latter’s expression profile and high conservation throughout evolution suggest a crucial role in embryonic as well as adult tissues. These two findings validate the predictive character of our library which constitutes a powerful tool to identify new thyroid developmental genes and new candidate genes for the study of the etiopathogenic mecanisms responsible for CH.

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