Congenital hypothyroidism (CH), a pediatric endocrine condition that results in early thyroid hormone (TH) insufficiency, is associated with visuospatial dysfunction suggestive of selective dorsal visual stream impairment. However, the ventral visual stream has not been adequately investigated in this population and so the effect of early TH insufficiency on development of the two streams had not been clearly established. This thesis used a comprehensive set of neuropsychological and experimental tests to assess higher-order visual functions in children and adolescents with CH compared with typically developing individuals. The results show that while CH is associated with poorer performance on tasks tapping into dorsal stream functions such as judgment of line orientation, spatial localization, three-dimensional block and two-dimensional mental construction, judgment of object location, and mental rotation, performance on typical ventral stream tasks such as identity discrimination, including abstract shapes, faces, and buildings, is relatively unimpaired. Thus this thesis establishes that the dorsal visual stream is selectively vulnerable to TH insufficiency. In addition to the investigating the nature of the higher-order visual problems in CH, this thesis explores the mechanism underlying these problems and assesses whether they result from organizational effects by early TH or activational effects by current TH levels. The data support the organizational mechanism and suggest that prenatal TH insufficiency results in irreversible changes to the dorsal visual stream due to the timing of dorsal stream development, which occurs earlier than ventral stream development and is thus more vulnerable to insult.

The hippocampus, which is a critical brain region for episodic autobiographical memory (AM), is particularly vulnerable to damage following periods of early thyroid hormone (TH) deficiency. Although numerous studies have examined AM performance in adult patients with hippocampal damage, no study has yet examined AM in children exposed to early TH deficiency, such as children with congenital hypothyroidism (CH) and offspring of women who were hypothyroid during pregnancy (HYPO). Given that both animal and human studies have shown that early TH deficiency results in significant hippocampal abnormalities and memory impairments, the purpose of this dissertation was to investigate the effects of early TH deficiency on AM and hippocampal structure and function during childhood. Study I examined AM performance in a large sample of typically developing children and adolescents in order to validate the use of the newly-developed Children’s Autobiographical Interview (CAI). In Study II, the CAI was used to investigate AM performance in children with early TH deficiency (i.e., CH and HYPO groups). Similar to the findings observed in adults with hippocampal damage, CH and HYPO groups both exhibited weaknesses in episodic AM, but not semantic AM, relative to controls. In addition, structural MRI revealed mild bilateral hippocampal volume reductions in HYPO, but not CH, which is consistent with animal models suggesting that early prenatal TH deficiency (i.e., HYPO) may be associated with greater abnormalities in hippocampal structure than postnatal TH deficiency (i.e., CH). Study III investigated children’s AM accuracy performance using a staged event and indicated that children with early TH deficiency had proportionally less accurate recollections of the staged event than controls. Importantly, smaller hippocampal volumes in both CH and HYPO groups predicted lower AM accuracy scores. Finally, in Study IV, functional MRI revealed that children with early TH deficiency exhibited abnormal (i.e., greater bilateral) hippocampal activation during episodic AM retrieval, but not during semantic AM retrieval, relative to controls, which may reflect neural compensation or may be a by-product of the degree of hippocampal damage. Overall, this dissertation provides critical new insight into the long-term effects of early TH deficiency on children’s AM performance and the hippocampus.

Congenital hypothyroidism (CH), a pediatric endocrine condition that results in early thyroid hormone (TH) insufficiency, is associated with visuospatial dysfunction suggestive of selective dorsal visual stream impairment. However, the ventral visual stream has not been adequately investigated in this population and so the effect of early TH insufficiency on development of the two streams had not been clearly established. This thesis used a comprehensive set of neuropsychological and experimental tests to assess higher-order visual functions in children and adolescents with CH compared with typically developing individuals. The results show that while CH is associated with poorer performance on tasks tapping into dorsal stream functions such as judgment of line orientation, spatial localization, three-dimensional block and two-dimensional mental construction, judgment of object location, and mental rotation, performance on typical ventral stream tasks such as identity discrimination, including abstract shapes, faces, and buildings, is relatively unimpaired. Thus this thesis establishes that the dorsal visual stream is selectively vulnerable to TH insufficiency. In addition to the investigating the nature of the higher-order visual problems in CH, this thesis explores the mechanism underlying these problems and assesses whether they result from organizational effects by early TH or activational effects by current TH levels. The data support the organizational mechanism and suggest that prenatal TH insufficiency results in irreversible changes to the dorsal visual stream due to the timing of dorsal stream development, which occurs earlier than ventral stream development and is thus more vulnerable to insult.

Thesis (Ph. D.)--University of Rhode Island, 2003. / Typescript. Includes bibliographical references (leaves 240-271).

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published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

Summary of the Doctoral Dissertation Biomedical Science, Medicine (07 B) The doctoral dissertation has been prepared at Kaunas University of Medicine during the period of 2000-2004. Scientific Supervisor: Prof. Dr. Romualdas Gailys (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07 B) The dissertation will be defended at the Medical Research Council of Kaunas University of Medicine. Chair: Prof. Habil. Dr. Dalia Pangonytė (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07 B) Members: Prof. Habil. Dr. Vaiva Lesauskaitė (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07 B) Prof. Habil. Dr. Laima Griciūtė (Vilnius University, Biomedical Sciences, Medicine – 07 B) Assoc. Prof. Dr. Antanas Sederevičius (Lithuanian Veterinary Academy, Biomedical Sciences, Veterinary Medicine – 12 B) Dr. Rimantas Žalinkevičius (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07 B) Official opponents: Dr. Birutė Žilaitienė (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07B) Assoc. Prof. Dr. Arvydas Laurinavičius (Vilnius University, Biomedical Sciences, Medicine – 07B) The dissertation will be defended at the open session of the Medical Research Council on the July 1st, 2005 in the auditorium of the Clinic of Pathology at Kaunas University of Medicine. Address: Eivenių str. 2, LT- 50009 Kaunas, Lithuania. The summary of the Doctoral Dissertation was sent out on May 31st, 2005. The Dissertation is available in the... [to full text]

The RET proto-oncogene encodes a receptor tyrosine kinase (RTK) that is widely expressed in neuroendocrine tissues and is essential for embryonic development of the kidney and enteric nervous system. Mutations leading to constitutive activation of the RET protein underlie various tumours of endocrine tissues. Conversely, loss-of-function mutations of RET lead to Hirschsprung disease, a congenital disorder characterized by a loss of enteric neurons throughout the colon and small intestine. Intracellular trafficking of RTKs through multiple cellular compartments has been shown to impact on downstream signalling. To date, the intracellular trafficking of RET has not been investigated. Here, we show that RET is rapidly internalized after activation and that trafficking to cytoplasmic endosomes plays an important role in downstream signalling. RET is alternatively spliced into multiple isoforms that are co-expressed in cells; therefore, we further investigated RET internalization in an isoform-specific context. This study revealed a number of differences between RET isoforms including differences in sub-cellular localization pre-activation, rate of internalization, and ability to recycle to the plasma membrane. Differential trafficking of RET isoforms alter their downstream signalling properties, providing an additional mechanism to explain the distinct contributions of RET isoforms to cellular processes. Finally, we investigated the impact of altered sub-cellular localization in the context of thyroid carcinoma. Activation of RET has been implicated in a number of thyroid tumours that differ in their inherent oncogenicity. We observed that altered subcellular localization of oncogenic forms of RET, RET/PTCs, enhance their oncogenicity. Interestingly, RET/PTC tumours are indolent and rarely metastasize compared to other RET-mediated forms of cancer. Further investigation revealed that RET/PTC oncogenes are expressed off relatively weak promoters, resulting in quantitatively less RET/PTC oncoprotein expression in these tumours compared to mutant RET expression in more aggressive cancers. Together, our results represent the first in-depth study of the trafficking properties of RET and indicate the importance of proper sub-cellular localization and trafficking in the maintenance of normal cell metabolism. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2009-11-19 22:51:47.38

The principle of the combined reversed-phase chromatographic electrochemical detection assay of the major serum thyroid hormones is demonstrated. The separation of 3,3',5-triiodothyronine (T(,3)), 3,3',5'-triiodothyronine (rT(,3)) and 3,5,3',5'-tetraiodothyronine (T(,4)) has been studied as a function of solvent strength, pH, temperature and ionic strength. Detection was carried out using a thin-layer electrochemical detection cell set at 1.500 V containing a new material, low temperature isotropic carbon, as a working electrode. This material was evaluated against carbon paste and using it, subnanogram detection limits were noted for the above analytes under defined conditions. Investigation of the feasibility of this analysis applied to 1.0 mL serum samples was carried out using a combined solvent extraction-cation exchange resin clean-up approach. The data indicate that under the defined conditions, elevated total T(,3) levels can be discerned and total T(,4) levels quantitated demonstrating the potential utility of this approach in screening thyrometabolic status.

The thyroid hormone system plays a major role in larval development, growth, and metabolism in fish. Therefore, any anthropogenic alteration in thyroid function could have dramatic effects on individual fitness. In this study Lake Sturgeon, Acipenser fulvescens, larvae were exposed to a commercially used organophosphate pesticide, chlorpyrifos (0, 5, 500 and 2000ng/L), from hatch until the onset of exogenous feeding (~12 days at 14C). The presence of thyroid follicles was first observed at 6 days post hatch (dph). Molecular expression of thyroid receptor α (TRα) increased from 3 to 12dph and then decreased from 12 to 21dph. TRα expression was also significantly higher in brain, liver and muscle at 67dph when compared to TRβ. Of the circulating hormones only free-T3 was consistently measured in larval homogenates from all development time-points sampled. Exposure to chlorpyrifos had no effect on growth or thyroid follicle morphology during the course of the experiment.