Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Thyroid hormones are essential for normal brain development. Therefore thyroid disease may be responsible for the onset of severe neurological disorders. The proper functioning of the maternal thyroid gland, especially during the early stages of pregnancy, plays an important role in ensuring that the offspring have normal brain and body development.We aimed to investigate the impact of experimental gestational hypothyroidism (EGH) on nociceptive threshold and motor activity in the offspring at different postnatal ages (7th, 15th, 23rd, 30th, 60th and 120th postnatal days; PND) in rats. EGH was induced with methimazole (MMI) 0.02% in drinking water from day 9 of gestation until birth. The offspring was assessed for thermal and mechanical nociception using the tail-flick test and vonFrey filaments. Rota-Rod test and grip strength were used to assess motor function. EGH reduced thermal, but not mechanical threshold at all ages studied (p <0.05). Differently, 60 days old females offspring from MMI-treated dams (f-OMTD) were not affected by EGH when tested in the tail-flick. Only males OMTD presented a deficient locomotor performance using the Rota-Rod test (p < 0.01 at 60th PND), and the grip strength meter (p < 0.05 at 120th PND), in comparison to offspring from water-treated dams (OWTD). In conclusion, EGH promotes hypersensitivity to noxious thermal, but not mechanical stimulus, whereas motor performance is reduced and thermal hypernociception remains present, both only in mature males OMTD, suggesting the presence of a protective factor in females. / Os hormônios tireoideanos são essenciais para o desenvolvimento normal do cérebro. Portanto, doenças da tireóide podem ser responsáveis pelo aparecimento de graves distúrbios neurológicos. O bom funcionamento da glândula tireóide materna, especialmente durante os primeiros meses da gravidez, desempenha um papel importante para garantir que os filhotes apresentem adequado desenvolvimento corporal e cerebral. No presente estudo, investigou-se o impacto do hipotireoidismo gestacional experimental (HGE) na sensibiliade mecânica e térmica e desempenho locomotor na prole em diferentes idades pós-natais (7, 15, 23, 30, 60 e 120 dias pós-natais; DPNs). O HGE foi induzido adicionando metimazol (MTZ), a uma concentração de 0,02%, em água potável a partir do dia 9 de gestação até o parto. A prole foi avaliada para sensibilidade térmica e mecânica através dos testes tail-flick e vonFrey, respectivamente. Os testes Rota-Rod e o Grip Strength Meter foram utilizados para avaliar a função motora da prole. Assim, nossos dados demonstraram que o HGE não alterou a sensibilidade mecânica, no entanto, reduziu a latência térmica até o 1º mês de vida dos filhotes (7, 15, 23 e 30 DPN). Aos 60 DPNs, somente os filhotes machos de mães tratadas com MTZ durante o período gestacional apresentaram redução na latência térmica (p<0,05). Acrescido a isto, estes mesmos machos apresentaram desempenho locomotor deficiente aos 60 DPNs e força de preensão reduzida aos 120 DPNs (p<0,01 e p<0,05, respectivamente), em comparação com filhotes de mães eutireóideas. As mesmas alterações não foram observadas na prole do sexo feminino. Em conclusão, o HGE não altera a sensibilidade mecânica da prole, porém promove hipersensibilidade a estímulos térmicos nocivos, sendo que, na fase adulta (60 DPN), apenas os machos são afetados. Ademais, o desempenho motor é reduzido somente em machos, sugerindo a presença de algum fator de proteção no sexo feminino.

A principal função da glândula tireoide é a produção dos hormônios T3 e T4, que promovem a regulação do consumo energético no organismo. O hipotireoidismo congênito (HC) é um distúrbio metabólico sistêmico, onde a produção de T3 e T4 no período neonatal é insuficiente. O HC por disormonogênese é uma doença causada por erros inatos na síntese de T3 e T4, com herança autossômica recessiva. Já foram descritas mutações nos genes NIS, SLC26A4, DUOX2, DUOXA2, TPO, TG e DEHAL-1. O defeito na organificação do iodeto (DOI) é o mais comum na disormonogênese, sendo a falha mais frequente na TPO, seguida pelas proteínas DUOX2 e DUOXA2. A TPO é responsável pela oxidação do iodeto, pela iodação da tireoglobulina e pelo acoplamento das tirosinas iodinizadas. Já foram descritas 70 mutações ao longo de todo o gene TPO. Por ser uma heme peroxidase, a TPO requer H2O2 para sua função. O principal núcleo catalítico gerador de H2O2 na tireoide é o complexo DUOX2/DUOXA2. Foram descritas 25 mutações no gene DUOX2 e uma única mutação no gene DUOXA2. Em estudo anterior, avaliamos pacientes com HC após os 3 anos de idade para estabelecimento do diagnóstico etiológico, através de dosagem de TG sérica, ultrassonografia, captação e mapeamento da tireoide com 131I. Sete pacientes apresentaram DOI. Nestes pacientes avaliamos o gene TPO e identificamos diversos SNPs já descritos na literatura. Um paciente apresentou a mutação p.Q660E em heterozigose, outro paciente o SNP p.R584Q em homozigose, e um terceiro paciente as alterações p.Q660E e p.584Q em heterozigose composta. Os objetivos deste estudo foram pesquisar mutações dos genes DUOX2 e DUOXA2 nos pacientes com DOI e realizar o estudo funcional da alteração p.R584Q na TPO. Para o estudo molecular, extraímos o DNA de leucócitos periféricos dos pacientes e seus familiares, seguido de amplificação por PCR, e sequenciamento automático, e os resultados comparados com as sequencias normais de cada gene (GenBank). Na análise funcional da alteração p.R584Q na TPO, células HeLa foram transfectadas com plasmídios pcDNA contendo o gene da TPO normal e alterado, e a atividade das proteínas produzidas pelas células foi avaliada pelo sistema AmplexRed. Análises in silico foram realizadas com os programas de bioanálise PolyPhen, MutationTaster, SIFT e PSIPRED. Ao final do estudo molecular, no gene DUOX2, identificamos 20 SNPs previamente descritos, incluindo o SNP funcional p.H678R (rs57659670), presente em heterozigose em 3 pacientes. Também identificamos a nova substituição p.A1087V em heterozigose em um paciente. De acordo com dados dos programas de bioanálise, a alteração p.A1087V é prejudicial e o SNP p.H678R é tolerável. No gene DUOXA2 identificamos 5 polimorfismos previamente descritos e nenhuma mutação. No estudo funcional, verificamos uma diminuição significativa da atividade da TPO portadora da alteração p.R584Q em comparação à proteína normal (5% de atividade residual; p=0,0193). De acordo com os dados dos programas de bioanálise, a alteração p.R584Q é prejudicial. Três pacientes não apresentaram alterações nas regiões estudadas dos genes TPO, DUOX2 e DUOXA2. As revisões dos dados clínicos e laboratoriais sugerem a presença de outras proteínas alteradas, como TG, Pendrina ou receptor do TSH. Um paciente apresentou a nova alteração p.A1087V na DUOX2 em heterozigose e nenhuma outra alteração nas regiões estudadas dos genes avaliados. Cogitamos a presença de alterações em regiões não avaliadas ou ainda a expressão monoalélica de DUOX2. O SNP funcional p.H678R na DUOX2 foi identificado em três pacientes com alterações na TPO: um com a alteração p.R584Q em homozigose, outro com a p.R584Q e a mutação p.Q660E em heterozigose composta. Estes dois pacientes apresentam os dois alelos da TPO alterados, justificando o DOI. O terceiro caso apresentou apenas a mutação p.Q660E em heterozigose, podendo apresentar alterações em regiões não avaliadas ou ainda a expressão monoalélica da TPO. Concluímos que definimos o diagnóstico molecular de 4 dos nossos pacientes, que apresentaram importantes alterações nos genes avaliados, e ressaltamos que a alteração p.R584Q na TPO provoca perda da atividade, causando DOI / The main role of the thyroid gland is to produce T3 and T4, which promote the regulation of body energy intake. Congenital hypothyroidism (CH) is a systemic metabolic disorder where T3 and T4 production during neonatal period is insufficient. CH due to dyshormonogenesis is a disease caused by inborn errors in T3 and T4 synthesis, with autosomal recessive inheritance. Mutations in NIS, SLC26A4, DUOX2, DUOXA2, TPO, TG and DEHAL-1 genes have been described. The iodide organification defect (IOD) is the most common cause of dyshormonogenesis, being the TPO defect the most frequent, followed by defects in DUOX2 and DUOXA2 proteins. TPO is responsible for iodide oxidation, tyrosine iodination and its coupling. Seventy mutations have been described throughout the gene. As a heme peroxidase, TPO requires H2O2 to its regular function. The main catalytic core for H2O2 generation in thyroid is the DUOX2/DUOXA2 complex. Twenty five mutations have been described in DUOX2 gene and only one mutation in DUOXA2 gene. In our previous study, we evaluated patients with CH after 3 years of age to establish their etiologic diagnosis, by combining serum TG, thyroid ultrasound, and radioiodide uptake with 131I. Seven patients were diagnosed with IOD. In these patients, we evaluated TPO gene and identified several already described SNPs. One patient had the p.Q660E mutation in heterozygous state, another patient had the SNP p.R584Q in homozygous state and a third one had p.Q660E and p.584Q in compound heterozygous state. The aims of this study were to search for mutations in DUOX2 and DUOXA2 genes in patients with IOD and perform a functional study of TPO p.R584Q change. For the molecular study, DNA was extracted from peripheral blood leukocytes of each patient and parents, followed by PCR, and automatic sequence, and the results were compared with normal sequences of each gene (GenBank). For functional analysis of TPO p.R584Q, HeLa cells were transfected with pcDNA plasmids containing normal and altered TPO gene and the protein activity was assessed by AmplexRed system. In silico analyzes were performed with the bioanalysis programs: PolyPhen, MutationTaster, SIFT and PSIPRED. At the end of the molecular study, in DUOX2 gene we identified 20 previously described SNPs, including the functional p.H678R SNP (rs57659670), present in heterozygous state in 3 patients. We also identified the new p.A1087V change in heterozygous state in one patient. According to bioassay programs datas, p.A1087V change is damage and p.H678R SNP is tolerable. In DUOXA2 gene we identified five previously described polymorphisms and no mutation. In TPO functional study, we observed a significant activity decrease of TPO p.R584Q compared to normal TPO (5% of activity; p=0.0193). According to bioassay programs datas, p.R584Q is damaging. Three patients showed no changes in TPO, DUOX2 and DUOXA2 genes studied regions. A review of clinical and laboratory data suggested the presence of other altered proteins, such as TG, Pendrin or TSH receptor. One patient had the new DUOX2 p.A1087V alteration in heterozygous state and no other changes in the studied regions of evaluated genes, suggesting that there could be changes in other nonevaluated regions or the monoallelic expression of DUOX2. The functional DUOX2 p.H678R SNP was identified in three patients with changes in TPO: one with p.R584Q change in homozygous state and another one with p.R584Q and p.Q660E in compound heterozygous state. These cases have the two alleles of TPO changed, justifying their IOD. A third case showed only the TPO p.Q660E mutation in heterozygous state. We speculate that the patient may present changes in regions nonevaluated or the monoallelic expression of TPO. We conclude that we defined the molecular diagnosis of four patients, that showed significant changes in evaluated genes, and that TPO p.R584Q change is functionally harmful, causing IOD

Made available in DSpace on 2016-03-15T19:39:56Z (GMT). No. of bitstreams: 1 Cyntia Moraes Teixeira.pdf: 299481 bytes, checksum: 9bb0d211bcfc9fdcd4b0b8dbed28d6e4 (MD5) Previous issue date: 2012-08-09 / Universidade Presbiteriana Mackenzie / Obesity has been considered epidemic in the whole world and is a risk factor for the development of hypertension, dyslipidemia, hyperglycemia, type 2 diabetes and hepatic steatosis. The increase of obesity in during pregnancy not only increases the risk of developing cardiovascular diseases but may also be related to abnormalities in the developing CNS of embryos, for example, reduction of potential long-term (LTP) in the hippocampus and neurogenesis . It is possible that the reduced levels of BDNF observed in these embryos, are involved with the injury in the processes of learning and memory observed in these animals. Studies also show that BDNF is reduced in fetuses of mothers with maternal subclinical hypothyroidism. These puppies have worsening neurological development, with deficits in long and short term memory. Here we evaluated whether maternal obesity may alter levels of BDNF and enzyme expression of type III deiodinase (D3) in the brains of pups, with consequent alteration of local levels of T3 to 7 °, 10 ° and 16 ° day-old post -natal. Our results showed that obesity reduced the expression of D3 on the 7th day of postnatal life of the offspring of obese mothers, but not in later days. There were no significant alterations in the levels of BDNF in any of the evaluated days. Our data suggest that it is possible that thyroid hormone is involved in neurophysiological abnormalities observed in offspring of obese rats. / A obesidade é uma epidemia de ordem mundial que é fator de risco para o desenvolvimento de hipertensão arterial, dislipidemia, hiperglicemia, diabetes tipo 2 e esteatose hepática. O aumento de obesidade em gestantes além de aumentar o risco do desenvolvimento de doenças cardiovasculares, também pode estar relacionado com anomalias no desenvolvimento do Sistema Nervoso Central dos embriões como, por exemplo, redução dos potenciais de longa duração (LTP) e da neurogênese no hipocampo. É possível que os níveis reduzidos de BDNF observados nestes embriões, estejam envolvidos com o prejuízo nos processos de aprendizado e memória exibidos por esses animais. Estudos também mostram que o BDNF se encontra reduzidos em fetos de mães com hipotiroidismo subclínico materno. Estes filhotes apresentam piora no desenvolvimento neurológico, demonstrando déficits na memória de longo e de curto prazo. O presente avaliou se a obesidade materna pode alterar os níveis de BDNF e a expressão da enzima desiodase do tipo III (D3) no cérebro dos filhotes, com consequente alteração dos níveis locais de T3 ao 7°, 10° e 16° dias de vida pós-natal. Os nossos resultados mostraram que a obesidade reduziu a expressão da D3 no 7º dia de vida pós-natal dos filhotes de mães obesas, mas não nos dias posteriores, sem alteração significativa nos níveis de BDNF. Não houve alteração significativa nos níveis de BDNF em nenhum dos dias avaliados. Os nossos dados sugerem que é possível que o hormônio tiroideano esteja envolvido nas alterações neurofisiológicas observadas em filhotes de ratas obesas.

Pendrin is an anion transporter that is expressed in several organs. In the thyroid gland, pendrin is localized at the apical pole of thyrocytes and it is responsible for the iodide efflux from thyrocytes into the colloid in the follicular lumen where iodide is organificated. The extrathyroidal expression was shown in the inner ear, kidney, placenta and mammary gland. Carriers of mutations in the pendrin gene (PDS, SLC26A4) display variable phenotypical features following the autosomal recessive manner of the inheritance: combined thyroid and hearing affection (Pendred syndrome - OMIM274600), nonsyndromic autosomal recessive neurosensory deafness (DFNB4 - OMIM600791) or isolated enlarged vestibular aqueduct (EVA - OMIM603545). The thyroid affection is usually manifested as euthyroid or hypothyroid goitre in the second decade of life. In a minority of patients, dyshormonogenesis is present at birth, and the disease is diagnosed in the frame of the nation-wide neonatal screening for congenital hypothyroidism.

Primär hypotyreos är i Sverige en folksjukdom som främst drabbar kvinnor i alla åldrar. Sjukdomens symtom är omfattande och kan ge allvarliga konsekvenser för patientens hälsa om sjukdomen inte upptäcks och behandlas i tid. Symptom som sjukdomen uppvisar påverkar patientens livskvalitet. Sjuksköterskans ansvar är att främja patientens livskvalitet genom att bland annat hjälpa individen med anpassningen till de förändringar som sjukdomen medför. Syftet med denna litteraturstudie är att belysa hur primär hypotyreos påverkar livskvalitet hos vuxna individer. Metoden är en litteraturstudie baserad på tio vetenskapliga artiklar. Resultatet: ångest och depression är vanligt förekommande besvär och orsakar mental ohälsa hos individen med primär hypotyreos. En del patienter upplever begränsningar i det dagliga livets aktiviteter, reducerad generell hälsa, sociala problem, minskad vitalitet samt emotionella begränsningar. Psykiska, fysiska samt sociala aspekter påverkar patientens livskvalitet. / Primary hypothyroidism is in Sweden a national disease that afflicts primarily women of all ages. The disease’s symptoms are extensive and can give serious consequences to the patient’s health if not detected and treated in time. This could greatly affect the patient’s quality of life. Nursing interventions are aimed at promoting the patient's quality of life through helping the individual with adaptation to changes caused by the disease. The aim was to illustrate how primary hypothyroidism affects the quality of life in adult patients. The method chosen was a literature review based on 10 scientific articles. The result showed that anxiety and depression are common problems that can cause mental illness in individuals with primary hypothyroidism. Patients could experience restrictions in activities in their daily life, reduced overall health, social problems, decreased vitality and emotional limitations. Psychological, physical and social aspects affect the patient’s quality of life.

6 Abstract Basis: This master's thesis deals with the issue of foods affecting thyroid function. The thyroid gland is an important endocrine organ involved in many bodily processes, it is completely dependent on external iodine intake and at the same time it is susceptible to some naturally occurring antinutritive substances. The main subject of research were therefore the sources of iodine and strumigenic substances in the diet and their occurrence in the diet of adults. The main sources for this thesis include the monograph Thyroid Gland, organized by Zdeňka Límanová, websites of professional institutions of the Ministry of Health of the Czech Republic and the World Health Organization and of course current studies dealing with this issue available in world health databases. The topic was chosen by the author on the basis of finding current topics in the field of nutrition, that have not yet been reserched by other students in the Nutrition Specialist field of study in recent years. Aims: The primary goal of the master's thesis was to examine and process current issues of thyroid function, especially in connection with the consumption of foods that affect this function. For this purpose, a questionnaire was compiled to obtain sufficient base and data to determine the average consumption of iodine and...

Small cell variant of medullary thyroid carcinoma is an extremely rare histologic entity with a paucity of data. As such, there is a lack of literature and clinical experience regarding this disease. In this report, we examine a case of small cell variant of medullary thyroid carcinoma that presented with intractable nausea, vomiting and diarrhea. While these symptoms were essentially refractory to the standard symptomatic treatment, further laboratory analysis revealed dramatically elevated calcitonin levels and mildly raised thyroid-stimulating hormone levels. Interestingly, repletion of thyroid hormone and treatment with lanreotide resulted in an abatement of our patient's symptoms. This temporal clinical improvement highly suggests a potential role involving thyroid-stimulating hormone and calcitonin levels in the pathogenesis of this disease, and consequently suggests a role for thyroxine in treating the associated gastrointestinal symptoms.

L’hypopituitarisme se définit par le déficit d’une ou plusieurs hormones hypophysaires.L’hypopituitarisme congénital est lié à des mutations de facteurs de transcriptionimpliqués dans le développement hypophysaire. Identifier les mécanismes et étiologiesd’hypopituitarisme congénital doit permettre d’améliorer les traitements des patients.Dans cette optique, ce travail a porté sur 3 aspects :Clarifier les mécanismes permettant la différenciation des lignées hypophysaires. Aucours du développement hypophysaire chez la souris, il existe un phénomène complexed’interaction entre 2 facteurs de transcription à homéodomaine paired (Prop1 et Hesx1),la voie Wnt-ßcaténine et les co-répresseurs de la famille Groucho/TLE. Ces interactionssont nécessaires à l’expression d’un autre facteur de transcription hypophysaire, Pit-1(Pou1f1), impliqué dans la différentiation des lignées hypophysaires somato-lactotropeset thyréotropes. Nous avons démontré in vitro, que les co-répresseurs de la famille TLEjouaient un rôle inhibiteur direct sur l’activation de l’early enhancer de POU1F1 à e12-e13, indépendamment de l’action de HESX1. Nos modèles de souris transgéniquesavec expression permanente de HESX1 et TLE3 permettent de mettre en évidence lerôle inhibiteur majeur de HESX1, et le rôle accessoire de TLE3. Les mutations dePROP1 étant à l’origine d’une expression persistante de HESX1 et TLE3, il est probablequ’ils jouent un rôle dans le déficit en sous-unité alpha observé chez les patientsdéficitaires en PROP1.Identifier et analyser la signification fonctionnelle de nouveaux variants alléliques dugène d’un facteur de transcription à homéodomaine LIM, LHX4. La mutation T99fs deLHX4 est à l’origine d’un phénotype hypophysaire très variable au sein d’une mêmefamille, en termes de déficits et de morphologie hypophysaires, et d’anomalies extrahypophysairesassociées. Les études fonctionnelles ont montré que cette mutation étaitresponsable d’un phénomène d’haplo-insuffisance. Cette nouvelle mutation permetd’enrichir le spectre phénotypique des patients chez lesquels doit être effectué unséquençage du gène LHX4 à la recherche d’étiologie de déficit hypophysaire combinémultiple.Identifier des mécanismes nécessaires au développement de l’axe thyréotrope. Dessouris exprimant une nouvelle recombinase Cre sous contrôle du promoteur de la Tshßont été croisées avec des souris transgéniques pour lesquelles les gènes de Pitx2 oud’Isl1 (2 facteurs de transcription impliqués dans le développement hypophysaire)étaient encadrés de séquences flox. Les modèles permettaient ainsi l’inactivation dePitx2 et Isl1 au sein des cellules thyréotropes au cours de l’embryogenèse. L’étudephénotypique retrouve un déficit de croissance compatible avec un déficit thyréotropepartiel en cas d’inactivation de Pitx2 : ce phénotype est probablement lié à unmécanisme compensateur assuré par PITX1, un facteur de transcription àhoméodomaine bicoïde possédant le même homéodomaine et domaine C terminal quePITX2. A l’inverse, l’inactivation de Isl& se traduit par un déficit thyréotrope complet. Lefait que les transcrits de l’ensemble des facteurs de transcription nécessaires audéveloppement de l’axe thyréotrope soient diminués dans ce modèle souligne le rôlemajeur de ISL1 dans la fonction et la maintenance de l’axe thyréotrope.Nos résultats permettent de mieux appréhender certains des nombreux mécanismes etfacteurs impliqués dans le développement hypophysaire chez la souris, et dans lapathologie hypophysaire chez l’homme. / Hypopituitarism is defined by one or several pituitary deficiencies. Congenital hypopituitarism is mostly due to transcription factors mutations. Our aims were to try to better identify some of the mechanisms involved in pituitary ontogenesis and pituitary diseases, mainly pituitary deficiencies: new pathways, new transcription factors, new mutations. - First we identified novel mechanisms necessary for the differenciation of the Pou1f1 lineages (ie somatolactotroph and thyrotroph cells). The role of TLE co-repressors is crucial, as they are able by themselves to inhibit the stimulatory actions of PROP1 on POU1F1 promoter. This is necessary to obtain a correct timing of differentiation during pituitary development (Carvalho, Brinkmeier, castinetti et al., Molecular Endocrinology, 2010). - Second, we showed the roles of 2 transcription factors, PITX2 and ISL1, in thyrotrophs maintenance and function. By using a new cre recombinase driven by the TSHb promoter, we managed to inactivate each of these transcription factors in the thyrotrophs. Inactivation of PITX2 led to a partial thyrotroph deficiency, counterbalanced by an overexpression of PITX1 (Castinetti et al., Molecular Endocrinology, submitted). Inactivation of ISL1 led to a complete thyrotroph deficiency (Castinetti et al., Molecular Endocrinology, in preparation). - Finally, we reported 1 new mutation of the LIM transcription factor LHX4, responsible for combined pituitary hormone deficiencies in a family. New phenotypic traits will help the physician improve the way to select which patients to screen for LHX4 mutations (Castinetti, Saveanu et al., JCEM, 2008).

Un ensemble des données cohérentes de la littérature plaide en faveur d'une relation entre une baisse d'activité de la voie de signalisation de la vitamine A, des altérations de la plasticité synaptique et des déficits mnésiques spécifiques associés au vieillissement. Une diminution de l'activité de cette voie de signalisation est également évoquée dans les processus neurodégénératifs caractéristiques de la maladie d'Alzheimer. Dans ce contexte, les objectifs de ce travail étaient de mieux comprendre les conséquences neuro-anatomiques et fonctionnelles d'une baisse d'activité de la voie de signalisation de la vitamine A. Notre approche expérimentale a mis en œuvre 2 modèles animaux, un modèle de carence vitaminique A qui induit spécifiquement une baisse d'activité de sa voie de signalisation et un modèle d'hypothyroïdie dont il a été montré qu'il induit aussi une hypoactivité de la voie de signalisation de la vitamine A. La démarche expérimentale conduite chez les rats carencés en vitamine A comporte deux volets : (i) un volet mettant en œuvre l’imagerie et la spectroscopie RMN, (ii) un volet moléculaire consacrée à l’étude de l’expression de gènes cibles des rétinoïdes impliqués dans le processus amyloïdogène. Les mesures ont été réalisées, d'une part, chez des animaux soumis à un régime dépourvu en vitamine A pendant 10 semaines et d'autre part, chez des animaux soumis à ce même régime pendant une durée de 13 ou 14 semaines. Une partie des animaux carencés a été traitée par de l'AR. Les résultats montrent que dès 10 semaines de carence, les animaux présentent une altération du métabolisme et de son action cellulaire de la vitamine A qui se traduit par (i) une diminution significative du taux de vitamine A sérique, (ii) une diminution du taux d'ARNm codant pour les récepteurs RAR, dans le cerveau entier, le striatum, l'hippocampe et de manière moins prononcée le cortex des animaux. Après 10 semaines de régime dépourvu en vitamine A, des modifications métaboliques ont été mises en évidence essentiellement dans le cortex. Elles se traduisent par une hausse du (i) NAA/Cr, marqueur de la densité neuronale corrigée par une administration d'AR, et (ii) du GSH/Cr, indicateur du potentiel antioxydant cellulaire dans cette structure. Au plan anatomique, un ralentissement de la croissance cérébrale a été observé dés la 7ème semaine de régime. Une diminution du volume hippocampique et une augmentation des espaces ventriculaires ont été observées à partir de 11 semaines de carence. Au plan moléculaire, aucune modification de l'expression du gène codant pour APP, ou du rapport APP770-751/APP695, considéré comme un indicateur précoce de la MA n'a été observée après 10 semaines de carence. Après 14 semaines de régime dépourvu en vitamine A, de profondes modifications métaboliques sont observées dans les trois structures à savoir le cortex, l’hippocampe et le striatum. Au plan moléculaire, les principaux résultats suggèrent un basculement du processus biochimique de dégradation de la protéine APP en faveur de la voie amyloïdogénique dans le cortex, et par voie de conséquence en faveur de la formation du peptide Aß. Cependant, aucune modification du taux protéique des peptides Aß n'a été mise en évidence dans le cortex et l'hippocampe des rats carencés. Le modèle d'hypothyroïdie que nous avons mis en oeuvre entraine bien une hypoactivité de la voie de signalisation de la T3, observée dans l'hippocampe des animaux et une diminution du taux d'ARNm codant pour RARß observée dans le cortex des rats hypothyroïdiens. Au plan moléculaire, l'augmentation du rapport APP770-751/APP695 a été observée chez les rats rendus hypothyroïdiens par rapport aux rats témoins. Comme chez les rats carencés en vitamine A, les indicateurs de la voie physiologique ne sont que très faiblement affectés chez les rats rendus hypothyroïdiens. / Some data reveal that retinoid hyposignalling, presumably resulting from decreased bioavailability of retinoid ligands naturally, was shown to result in aging-related synaptic plasticity and long term potentiation (LTP) alterations as well as in aging-related decline of cognitive function. Moreover, genetic, metabolic and dietary evidence has been provided for a defective retinoid metabolism in Alzheimer disease (AD). Thus, key steps of the amyloid production process are under the control of proteins whose expression is positively regulated by RA in vitro. In this context, the aims of this work were to better understand neuro-anatomical and functionnal consequences of retinoid signaling brain hypoactivity. Our experimental method uses two animal models: a Vitamin A deficiency model which induce especially an hypoactivity of retinoid pathway, and an hypothyroid model which was also characterized by an hypoactivity of retinoid pathway. In the fisrt model, two main approch were used : (i) an NMR imaging and spectroscopy approach, (ii) a molecular approach to study expression of retinoid target genes implicated in amyloidogenic process. NMR results showed that VAD induces severe anatomic and metabolic disorders in particular a slowing of brain growth, hippocampus atrophy, and a decrease of NAA/Cr, marker of neuronal density which was observed in cortex, hippocampus and striatum. Molecular results reveal a vitamin A deficiency-related dysregulation of the amyloid pathway in the cortex of rats, which is known to be the first brain area altered by AD development. In this area, 14 weeks of deprived diet induces physiological dysregulation in the modulation of RA target genes leading to an increased amount of ADAM10, BACE and PS1, with some modifications in amyloidogenic pathway but without increased amount of Aß peptides. In hypothyroid model, molecular results suggests that adult onset-hypothyroidism may induce the amyloidogenic pathway of APP processing by increasing activity of ß and ?secretases and levels of amyloid peptides mainly in hippocampus. Together these data argue for the idea that hypoactivity of retinoid signalling which occurs naturally with aging could be a factor participating in accelerating aging and that hypothyroidism that become more prevalent with advancing age, could increase, via a hyposignaling of T3 pathway, the vulnerability of amyloidogenic pathway of APP processing as well as of other clinical symptoms of AD.

Diplomová práce Miroslav Zůna 3 Author's first name and surname: Miroslav Zůna, BA. Title of the master thesis: Changes of thermal thresholds in patients treated with hypothyroidism. Department: Department of Physiotherapy and Sports Medicine Supervisor: Hana Marčišová, MA. The year of presentation: 2013 Abstract: Disorders of thyroid gland together with diabetes are most common endocrine diseases in Czech Republic and worldwide, too. Myopathy and neuropathy, caused by reduced amount of thyroid hormones, are mentioned in current literature, however pathaphysiological mechanisms stay unclear. To evaluate the state of small nerve fibers that should be affected first, we use thermal threshold testing, setting the thermal threshold for warm and cold stimuli in different locations. Patients with hypothyroidism show in most of the measured locations higher thermal threshold than that of the control group, however these results are not significant. Significant change of thermal sensation of cold stimulus is demonstrated in location thenar. Patients with hypothyroidism also have a higher degree of inaccuracy detection of thermal stimuli. A greater number of significant conclusions can not seem to reach for a small number of probands participating in our study or due to ongoing therapy and the resulting normal state...