Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-21T12:29:23Z No. of bitstreams: 1 fabianadefariaghetti.pdf: 2678682 bytes, checksum: 4f41f688b7803865f93dd37611975999 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T18:44:48Z (GMT) No. of bitstreams: 1 fabianadefariaghetti.pdf: 2678682 bytes, checksum: 4f41f688b7803865f93dd37611975999 (MD5) / Made available in DSpace on 2016-01-25T18:44:48Z (GMT). No. of bitstreams: 1 fabianadefariaghetti.pdf: 2678682 bytes, checksum: 4f41f688b7803865f93dd37611975999 (MD5) Previous issue date: 2014-03-27 / Pacientes com hipotireoidismo subclínico (HSC) possuem maior risco para mortalidade cardiovascular. Uma das possíveis explicações para esse desfecho seria a piora da função vascular. Porém, não são conhecidos os efeitos do HSC no comportamento hemodinâmico durante manobra fisiológica de estresse mental. O objetivo desse estudo foi investigar o comportamento hemodinâmico de mulheres com hipotireoidismo subclínico durante estresse mental. Foram avaliadas 20 mulheres com HSC (Grupo HSC) e 21 eutireoidianas (Grupo Controle), pareadas por idade (37±11 vs. 38±10 anos, p=0,699, respectivamente) e índice de massa corporal (26±5 vs. 25±5 kg/m2, p=0,462, respectivamente). O fluxo sanguíneo muscular (FSM), avaliado pela pletismografia de oclusão venosa, a frequência cardíaca (FC) e a pressão arterial (PA), medidas pelo Dixtal2023, foram registrados simultaneamente durante 3 minutos de basal, seguidos de 3 minutos de estresse mental (Stroop Color Word Test). A condutância vascular do antebraço (CVA) foi calculada pela divisão do FSM pela pressão arterial média multiplicada por 100. Foram utilizados os testes t de Student e ANOVA, adotando significativo p<0,05. O grupo HSC apresentou níveis significativamente maiores do hormônio estimulador da tireoide (7,57±3,17 vs. 2,10±0,88 mU/L, p<0,001). No basal os grupos HSC e Controle foram semelhantes para FC (67±8 vs. 67±10, p=0,126, respectivamente), pressão arterial sistólica (130±11 vs. 128±10 mmHg, p=0,851, respectivamente), pressão arterial diastólica (70±7 vs. 68±6, p=0,527, respectivamente), pressão arterial média (90±8 vs. 88±7, p=0,664, respectivamente), FSM (2,50±0,79 vs. 2,55±0,71 ml/min/100ml, p=0,905, respectivamente) e CVA (2,80±0,90 vs. 2,92±0,88 unidades, p=0,952, respectivamente). Durante todo o teste de estresse mental os grupos HSC e Controle aumentaram significativamente a FC (efeito tempo, p<0,001), a PA (efeito tempo, p<0,001), o FSM (efeito tempo, p<0,001) e CVA (efeito tempo, p<0,001) em relação ao basal. Porém, o FSM e a CVA foram significativamente menores no grupo HSC durante o primeiro (FSM: 3,66±0,96 vs. 4,66±1,61 ml/min/100ml, p=0,018, tamanho do efeito=0,78; CVA: 3,95±1,08 vs. 5,19±1,96 unidades, p=0,010, tamanho do efeito=0,81;) e segundo (FSM: 3,55±1,01 vs. 4,62±2,27 ml/min/100ml, p=0,018, tamanho do efeito=0,65; CVA: 3,75±1,07 vs. 4,92±2,37 unidades, p=0,020, tamanho do efeito=0,68) minutos do teste de estresse mental. Desta forma concluímos que mulheres com HSC possuem, durante estresse mental, FC e PA preservadas, porém FSM e CVA prejudicados. / Patients with subclinical hypothyroidism (SCH) have a higher risk of cardiovascular mortality. One possible explanation for this outcome may be a worsening of vascular function. However, the effects of SCH in hemodynamic response during mental stress physiological maneuver are not known. We hypothesized that women with HSC have impaired peripheral blood flow and peripheral vascular conductance during mental stress. We evaluated 20 women with SCH (SCH Group) and 21 euthyroid (Control Group) women, matched for age (37±11 vs. 38±10 years, p=0.699) and body mass index (26±5 vs. 25±5kg/m2, p=0.462). The muscle blood flow (MBF) (venous occlusion plethysmography), heart rate (HR) and blood pressure (BP) (Dixtal2023) were evaluated simultaneously during 3 min-baseline followed by 3-min of mental stress test (Stroop Color Word Test). Forearm vascular conductance (FVC) was calculated by dividing MBF by the blood pressure mean. Student t test and ANOVA were used, adopting significant p<0.05. The SCH group had greater TSH levels (7.57±3.17 vs. 2.10±0.88 mU/L, p<0.001). In baseline the groups HSC and Control were similar to HR (67±8 vs. 67±10, p=0.126), systolic blood pressure (130±11 vs. 128±10 mmHg, p=0.851), diastolic blood pressure (70±7 vs. 68±6, p=0.527), mean blood pressure (90±8 vs. 88±7, p=0.664), MBF (2.50±0.79 vs. 2.55±0.71ml/min/100ml, p=0.905) and FVC (2.80±0.90 vs. 2.92±0.88 units, p=0.952). During all mental stress test the groups SCH and Control increased significantly HR (time effect, p<0.001), BP (time effect, p<0.001), MBF (time effect, p<0.001) and FVC (time effect, p<0.001) compared with baseline. However, MBF and FVC were significantly lower in SCH group during first (MBF: 3.66±0.96 vs. 4.66±1.61 ml/min/100ml, p=0.018, effect size=0.78; FVC: 3.95±1.08 vs. 5.19±1.96 unidades, p=0.010, effect size=0.81) and second (MBF: 3.55±1.01 vs. 4.62±2.27 ml/min/100ml, p=0.018, effect sixe=0.65; FVC: 3.75±1.07 vs. 4.92±2.37 unidades, p=0.020, effect size=0.68) minuts of mental stress test. In conclusion women with SCH compared to euthyroid women have preserved HR and BP, however impaired MBF and FVC during mental stress.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18142号 / 医博第3862号 / 新制||医||1002(附属図書館) / 31000 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山田 亮, 教授 小杉 眞司, 教授 松田 文彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

yes / Background: The incidence of self-reported premature hair graying (PHG) seems to be on the rise. PHG has a profound impact on the patient's quality of life. It remains an incompletely understood etiology with limited and modest treatment options. Aim: The evaluation of the demographic and clinical profile of patients with premature canities, and exploration of the association of this entity with certain systemic disorders suspected to be related to its etiology. Methods: Seventy-one cases of premature canities (onset noticed by patients before 25 years of age) presenting to an urban skin clinic in Gurugram, India, between September 2012 and September 2015 with this complaint were retrospectively analyzed. The patient records were retrieved that provided details of the onset, duration and pattern of involvement, history, and examination findings (scalp, cutis, and general physical). Since all these patients had been screened for anemia, thyroid disorder, fasting blood glucose, and Vitamin B12 levels at the time of presentation, these parameters were also available for analysis. Results: The mean age at onset of graying was 10.2 ± 3.6 years (range: 5–19 years), with an almost equal gender distribution. The earliest age of onset recorded was 5 years. A positive family history of PHG (at least one of the biological parents or siblings) was obtained in 64 (90.1%) of the cases. The temporal regions of the scalp (35.2%) were most commonly involved followed by the frontal region (18.3%). Hypovitaminosis B12 and hypothyroidism showed significant association with the disorder, whereas anemia, serum ferritin, and fasting blood glucose did not. Conclusion: The age of onset of hair graying can be as low as 5 years. Temporal and frontal areas are the most commonly involved sites. A strong family history, Vitamin B12 deficiency, and hypothyroidism are strongly associated with PHG. Larger case–control studies are mandated for discerning the correlation of these and other risk factors with PHG.

Background: Canine hypothyroidism is thought to cause abnormalities in glucose homeostasis, but the effect on glucose tolerance and insulin sensitivity has not been determined to date. Hypothesis/Objectives: The purpose of the study was to investigate whether hypothyroidism has an effect on glucose tolerance and insulin sensitivity in dogs. We hypothesized that hypothyroidism causes insulin resistance. Animals: Sixteen euthyroid bitches were randomly selected and allocated into two groups. In 8 dogs, hypothyroidism was induced by administration of 1 mCi/kg I-131. Experiments were performed on non-anesthetized, fasted dogs in anestrous approximately 12 months after hypothyroidism was induced. Methods: The insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and minimal model analysis were used to determine basal insulin and glucose concentrations, acute insulin response to glucose (AIRg), insulin sensitivity (SI), glucose effectiveness (SG) and the disposition index (DI). Results: In the hypothyroid group, basal glucose concentrations were mildly decreased (P = 0.0079), whereas basal insulin was increased (P = 0.019). Insulin sensitivity was reduced in the hypothyroid group (P<0.001), whereas AIRg was higher (P=0.01). Other parameters were not different between groups. Conclusions/Clinical Importance: Hypothyroidism negatively affects glucose homeostasis by inducing insulin resistance. In hypothyroid dogs, the disposition index (insulin sensitivity x insulin secretion) remained unchanged due to a compensatory increase in insulin secretion, thereby maintaining glucose tolerance. In cases with impaired insulin secretion, such as canine diabetes mellitus, concurrent hypothyroidism can have important clinical implications in the successful management of the disease. / Master of Science

INTRODUÇÃO: No Brasil, são poucos os estudos sobre a freqüência das doenças tireoidianas e a maioria limita-se a populações específicas. OBJETIVOS: O objetivo principal deste estudo é correlacionar função tireoidiana subclínica a aspectos ultra-sonográficos em mulheres que realizaram rastreamento para função tireoidiana em local de trabalho. MÉTODOS: Estudo transversal de rastreamento com 135 mulheres de 40 anos ou mais, funcionárias da Universidade de São Paulo. Todas as participantes responderam a questionário específico, foram submetidas à mensuração de medidas antropométricas e da pressão arterial, tiveram uma amostra de sangue colhida para avaliação de função tireoidiana e anticorpos anti-tireoperoxidase, glicemia de jejum, colesterol total, HDL-colesterol, triglicérides e a proteína C ultra-sensível e foram submetidas à ultrasonografia da tireóide. Em uma subamostra do estudo foi realizada punção aspirativa por agulha fina guiada por ultra-sonografia de nódulos tireoidianos que preenchiam critérios de punção. RESULTADOS: As freqüências de hipotireoidismo e hipertireoidismo subclínico foram, respectivamente, 7,4% e 2,2%. A frequência de função tireoidiana normal foi 90,4%. Os valores médios de TSH foram diferentes nestes três grupos (P < 0,0001). Os níveis de anti-TPO foram significativamente diferentes entre os grupos, sendo mais elevados nos dois grupos de doença subclínica (P < 0,0001). O volume médio da tireóide no grupo do hipotireoidismo subclínico foi 8,9 ± 5,2 cm3, seguido pelo grupo do hipertireoidismo subclínico (8,9 ± 1,9 cm3) e pelo grupo das mulheres com função tireoidiana normal (7,7 ± 2,5 cm3) (P= 0,32). Não houve diferenças significativas entre os três grupos quanto à hipoecogenicidade da tireóide (P = 0,64). Entretanto, a ecotextura tireoidiana foi significativamente diferente entre os grupos (P = 0,02). Não foram encontradas diferenças significativas entre os grupos quanto à presença de nódulos císticos, sólidos ou mistos, nem quanto ao número médio de nódulos nas participantes que tinham algum nódulo à ultra-sonografia. Em 14% das mulheres houve indicação de biópsia dos nódulos e em duas foi diagnosticado carcinoma papilífero (1,4% da amostra). Houve uma associação entre ecotextura heterogênea e aumento dos níveis de anti-TPO (P < 0,0001) e uma associação limítrofe entre hipoecogenicidade e presença de anti-TPO (P = 0,051). O volume médio da tireóide no grupo das pacientes com anti-TPO elevado foi de 9,5 ± 4,5 cm3 e no grupo das pacientes com anti-TPO normal foi de 7,5 ± 2,5 cm3 (P = 0,02). A função tireoidiana e os aspectos ultra-sonográficos das mulheres procedentes de zona de bócio endêmico na infância não foram estatisticamente diferentes dos resultados encontrados em mulheres procedentes de zonas iodo-suficientes. CONCLUSÃO: O estudo mostrou associação entre função tireoidianasubclínica e alteração da ecotextura da tireóide em amostra de funcionárias da Universidade de São Paulo submetidas a rastreamento de função tireoidiana em local de trabalho. Níveis elevados de anti-TPO se associaram à alteração da ecotextura e ecogenicidade. Não houve diferenças em relação ao perfil de função tireoidiana ou aos achados ultra-sonográficos nas mulheres quando estratificadas de acordo com a procedência remota. / INTRODUCTION: In Brazil, there are few studies on the frequency of thyroid diseases and the majority is limited to specific populations. OBJECTIVE: The goal of this study is to correlate subclinical thyroid function to ultrasound characteristics in a sample of women submitted to screening of thyroid function at worksite. METHODS: Cross-sectional screening study with 135 women aged 40 years or older, all of them civil servants, working at Universidade de São Paulo. All the women answered specific questionnaires, had anthropometric variables and blood pressure measured, blood analyzed for total-cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, fasting glucose, thyroid-stimulating hormone (TSH), free-thyroxine (free-T4), antithyreoperoxidase antibodies (anti-TPO), high-sensitive C reactive protein (hsCRP) and they underwent a thyroid ultrasound. An ultrasound-guided fine needle aspiration biopsy of thyroid nodules was performed in a sub-sample of this group. RESULTS: The frequency of subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, 7,4% e 2,2%. The frequency of normal thyroid function was 90,4%. The mean values of TSH were different among the three groups (P < 0,0001). The levels of anti-TPO were significantly different among the groups, with higher levels within the two subclinical disease groups (P < 0,0001). The average thyroid volume within the subclinical hypothyroidism group was 8,9 ± 5,2 cm3, followed by the subclinical hyperthyroidism group with 8,9 ± 1,9 cm3 average volume and lastly by the normal thyroid function group with 7,7 ± 2,5 cm3 average volume (P= 0,32). There were no significant differences among the three groups regarding thyroid hypoechogenicity (P = 0,64). However, thyroid echotexture was significantly different among the groups (P = 0,02). There were no meaningful differences among the groups neither for the presence of cystic lesions, solid or mixed nodules nor for the average number of nodules of any kind within the group of women with thyroid nodules. Fourteen percent of the women had a nodule biopsy indication and 2 were diagnosed with papillary carcinoma (1,4% of the sample). There was an association between heterogeneous echotexture and high levels of anti-TPO (P < 0,0001) and a borderline association between hypoechogenicity and the presence of anti- TPO (P=0,051). The group with the high levels of anti-TPO showed a mean thyroid volume of 9,5 ± 4,5 cm3 and the group with normal levels of anti-TPO showed a mean thyroid volume of 7,5 ± 2,5 cm3 (P = 0,02). The thyroid function and the ultrasonographic aspects of the women from endemic areas in childhood were not statistically different from the results found in women from iodine sufficient areas. CONCLUSION: This study demonstrated the association between subclinical thyroid function and altered thyroid echotexture in a sample of female civil servants working at Universidade de São Paulo submitted to screening of thyroid function at worksite. It was demonstrated that high levels of anti-TPO were associated with thyroid echotexture and echogenicity alterations. There were no differences relating to the thyroid function profile or regarding the ultrasonographic findings among the women when classified according to their origin.

INTRODUÇÃO: No Brasil, são poucos os estudos sobre a freqüência das doenças tireoidianas e a maioria limita-se a populações específicas. OBJETIVOS: O objetivo principal deste estudo é correlacionar função tireoidiana subclínica a aspectos ultra-sonográficos em mulheres que realizaram rastreamento para função tireoidiana em local de trabalho. MÉTODOS: Estudo transversal de rastreamento com 135 mulheres de 40 anos ou mais, funcionárias da Universidade de São Paulo. Todas as participantes responderam a questionário específico, foram submetidas à mensuração de medidas antropométricas e da pressão arterial, tiveram uma amostra de sangue colhida para avaliação de função tireoidiana e anticorpos anti-tireoperoxidase, glicemia de jejum, colesterol total, HDL-colesterol, triglicérides e a proteína C ultra-sensível e foram submetidas à ultrasonografia da tireóide. Em uma subamostra do estudo foi realizada punção aspirativa por agulha fina guiada por ultra-sonografia de nódulos tireoidianos que preenchiam critérios de punção. RESULTADOS: As freqüências de hipotireoidismo e hipertireoidismo subclínico foram, respectivamente, 7,4% e 2,2%. A frequência de função tireoidiana normal foi 90,4%. Os valores médios de TSH foram diferentes nestes três grupos (P < 0,0001). Os níveis de anti-TPO foram significativamente diferentes entre os grupos, sendo mais elevados nos dois grupos de doença subclínica (P < 0,0001). O volume médio da tireóide no grupo do hipotireoidismo subclínico foi 8,9 ± 5,2 cm3, seguido pelo grupo do hipertireoidismo subclínico (8,9 ± 1,9 cm3) e pelo grupo das mulheres com função tireoidiana normal (7,7 ± 2,5 cm3) (P= 0,32). Não houve diferenças significativas entre os três grupos quanto à hipoecogenicidade da tireóide (P = 0,64). Entretanto, a ecotextura tireoidiana foi significativamente diferente entre os grupos (P = 0,02). Não foram encontradas diferenças significativas entre os grupos quanto à presença de nódulos císticos, sólidos ou mistos, nem quanto ao número médio de nódulos nas participantes que tinham algum nódulo à ultra-sonografia. Em 14% das mulheres houve indicação de biópsia dos nódulos e em duas foi diagnosticado carcinoma papilífero (1,4% da amostra). Houve uma associação entre ecotextura heterogênea e aumento dos níveis de anti-TPO (P < 0,0001) e uma associação limítrofe entre hipoecogenicidade e presença de anti-TPO (P = 0,051). O volume médio da tireóide no grupo das pacientes com anti-TPO elevado foi de 9,5 ± 4,5 cm3 e no grupo das pacientes com anti-TPO normal foi de 7,5 ± 2,5 cm3 (P = 0,02). A função tireoidiana e os aspectos ultra-sonográficos das mulheres procedentes de zona de bócio endêmico na infância não foram estatisticamente diferentes dos resultados encontrados em mulheres procedentes de zonas iodo-suficientes. CONCLUSÃO: O estudo mostrou associação entre função tireoidianasubclínica e alteração da ecotextura da tireóide em amostra de funcionárias da Universidade de São Paulo submetidas a rastreamento de função tireoidiana em local de trabalho. Níveis elevados de anti-TPO se associaram à alteração da ecotextura e ecogenicidade. Não houve diferenças em relação ao perfil de função tireoidiana ou aos achados ultra-sonográficos nas mulheres quando estratificadas de acordo com a procedência remota. / INTRODUCTION: In Brazil, there are few studies on the frequency of thyroid diseases and the majority is limited to specific populations. OBJECTIVE: The goal of this study is to correlate subclinical thyroid function to ultrasound characteristics in a sample of women submitted to screening of thyroid function at worksite. METHODS: Cross-sectional screening study with 135 women aged 40 years or older, all of them civil servants, working at Universidade de São Paulo. All the women answered specific questionnaires, had anthropometric variables and blood pressure measured, blood analyzed for total-cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, fasting glucose, thyroid-stimulating hormone (TSH), free-thyroxine (free-T4), antithyreoperoxidase antibodies (anti-TPO), high-sensitive C reactive protein (hsCRP) and they underwent a thyroid ultrasound. An ultrasound-guided fine needle aspiration biopsy of thyroid nodules was performed in a sub-sample of this group. RESULTS: The frequency of subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, 7,4% e 2,2%. The frequency of normal thyroid function was 90,4%. The mean values of TSH were different among the three groups (P < 0,0001). The levels of anti-TPO were significantly different among the groups, with higher levels within the two subclinical disease groups (P < 0,0001). The average thyroid volume within the subclinical hypothyroidism group was 8,9 ± 5,2 cm3, followed by the subclinical hyperthyroidism group with 8,9 ± 1,9 cm3 average volume and lastly by the normal thyroid function group with 7,7 ± 2,5 cm3 average volume (P= 0,32). There were no significant differences among the three groups regarding thyroid hypoechogenicity (P = 0,64). However, thyroid echotexture was significantly different among the groups (P = 0,02). There were no meaningful differences among the groups neither for the presence of cystic lesions, solid or mixed nodules nor for the average number of nodules of any kind within the group of women with thyroid nodules. Fourteen percent of the women had a nodule biopsy indication and 2 were diagnosed with papillary carcinoma (1,4% of the sample). There was an association between heterogeneous echotexture and high levels of anti-TPO (P < 0,0001) and a borderline association between hypoechogenicity and the presence of anti- TPO (P=0,051). The group with the high levels of anti-TPO showed a mean thyroid volume of 9,5 ± 4,5 cm3 and the group with normal levels of anti-TPO showed a mean thyroid volume of 7,5 ± 2,5 cm3 (P = 0,02). The thyroid function and the ultrasonographic aspects of the women from endemic areas in childhood were not statistically different from the results found in women from iodine sufficient areas. CONCLUSION: This study demonstrated the association between subclinical thyroid function and altered thyroid echotexture in a sample of female civil servants working at Universidade de São Paulo submitted to screening of thyroid function at worksite. It was demonstrated that high levels of anti-TPO were associated with thyroid echotexture and echogenicity alterations. There were no differences relating to the thyroid function profile or regarding the ultrasonographic findings among the women when classified according to their origin.

Tao Kin Pong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 144-152). / Abstracts in English and Chinese. / Chapter i. --- Cover page --- p.1 / Chapter ii. --- Table of contents --- p.2 / Chapter iii. --- Abstract of thesis (English version and Chinese Version) --- p.4 / Chapter iv. --- Acknowledgements --- p.8 / Chapter v. --- Abbreviations --- p.9 / Chapter 1. --- Introduction / Interstitial tissue and Leydig cells --- p.11 / Seminiferous tubules --- p.11 / "Male germ cell line and spermatogenesis (Mitotic, Meiotic and Post-meiotic)" --- p.12 / Sertoli cells --- p.14 / Specialized organizations of junction present in testis --- p.15 / Dynamic nature of Sertoli-Sertoli & Sertoli-germ cell junctions --- p.16 / Role of proteases and protease inhibitors in male gametogenesis --- p.17 / Proteases and Proteases Inhibitors expressed in testis --- p.18 / Hormonal control of spermatogenesis --- p.19 / Hypothyroidism and testis development --- p.21 / Genes to be studied: / Proteases --- p.22 / Proteases Inhibitors --- p.27 / Other spermatogenesis related genes --- p.30 / Chapter 2. --- Objectives --- p.32 / Chapter 3. --- Materials and Methods / Animal treatments and tissue collection --- p.33 / RNA preparation --- p.34 / RT-PCRs --- p.35 / Real-time PCRs --- p.35 / Data manipulations and Statistics --- p.36 / Primer sequences used in this experiment --- p.37 / Chapter 4. --- Results / "Effect of neonatal hypothyroidism on developmental profile of body weight, absolute and relative testicular weight" --- p.40 / Developmental transcription profiles of genes under normal and hypothyroidism --- p.43 / Screening Data --- p.78 / Expression of non-spermatogenic genes at neonatal age --- p.88 / Responsiveness of gene transcription after thyroxin replacement --- p.89 / Changes of gene expression under different hypothyroid regimens --- p.97 / Chapter 5. --- Discussion / Changes in testicular size under hypothyroidism --- p.107 / Five patterns of transcription profile --- p.107 / "Suggestion on the role of ""MEIOTIC"" proteases and inhibitors" --- p.111 / "Suggestion on the role of ""POST-MEIOTIC"" proteases and inhibitors" --- p.113 / "Explanations on ""SOMATIC"" genes" --- p.114 / "Explanations on ""MITOTIC"" genes" --- p.115 / Explanations on the un-clustered pattern --- p.116 / Explanations on the age down-regulated group --- p.116 / Proposed clustering of genes according to their transcription profile --- p.117 / "Expression of some ""non-spermatogenic"" genes before puberty" --- p.123 / Neonatal hypothyroidism as a model for studying reproductive physiology --- p.125 / Different components of spermatogenesis --- p.127 / Chapter I. --- Roles of nuclear and chromatin related genes in assisting meiosis --- p.128 / Chapter II. --- Roles of specific transcription regulators in assisting gene selection --- p.129 / Chapter III. --- Role of signal transduction molecules for translation and activation --- p.131 / Chapter IV. --- Role of proteases and inhibitors for matrix and junctions dynamics --- p.132 / The somatic proteases and inhibitors system in the testis --- p.133 / Spermatogenic proteases and inhibitors system --- p.134 / Chapter V. --- Role of matrix and junctional molecules in intercellular interactions --- p.137 / Chapter VI. --- Role of cytoplasmic motors in cellular movement --- p.139 / Chapter 6. --- Conclusion / Proposed story of spermatogenesis - involvement of proteases and inhibitors --- p.140 / Future Direction --- p.141 / Chapter 7. --- References --- p.144

Introdução: O hipotireoidismo congênito é a causa mais comum de retardo mental evitável em crianças, sua incidência varia de 1:2000 a 1:3000 nascidos vivos. É estimado que 15-20% dos casos de HC são conseqüentes de falhas na síntese dos hormônios tireoidianos. Entre as alterações genéticas mais freqüentes destaca-se o defeito na atividade da tireoperoxidase. Objetivos: rastrear mutações em duas pacientes com HC, com defeito parcial de incorporação de iodeto e verificar o efeito funcional de alterações do gene da tireperoxidase. Casuística e métodos: duas pacientes com HC, bócio e diagnóstico molecular não conhecido. Amostras de sangue periférico e de tecido tireoidiano das pacientes e amostras de DNA de indivíduos controles. Sequenciamento dos genes TPO, DUOX2 e DUOXA2. Análise da expressão gênica de TPO, TG, NKX2.1, PDS, PAX8, NIS e rTSH por PCR bem tempo real. Avaliação da expressão de luciferase sob controle do promotor da TPO e avaliação da atividaede da TPO do tecido as pacientes. Resultados: Nas pacientes foi identificada a alteração -95G>T, em homozigose, na região promotora da TPO. Verificamos diminuição da atividade enzimática da TPO no tecido tireoideano das pacientes e diminuição da expressão do RNAm desse gene. Também se encontrou diminuída a expressão dos genes NKX2.1 e PAX8. Já os genes TG, rTSH, PDS, NIS, a expressão do RNAm apresentou-se aumentada. A análise funcional da alteração -95G>C não mostrou diminuição da expressão do gene repórter. Conclusão: O HC das pacientes deve-se a diminuição da atividade enzimática da TPO, contudo alterações de sequência não foram encontradas no gene da TPO que expliquem a diminuição da atividade. Alterações epigenéticas ou nos introns no gene da TPO poderiam explicar o HC das pacientes. / Introduction: Congenital hypothyroidism is the most common cause of preventable mental retardation in children, its incidence varies from 1:2000 to 1:3000 live births. It is estimated that 15-20% of cases of CH are consistent failures in the synthesis of thyroid hormones. Among the most frequent genetic changes highlight the defect in the activity of thyroid peroxidase. Objectives: Identify mutations in two patients with CH and partial defect in iodide incorporation and verify the functional effect of changes in gene tireperoxidase. Methods: Two patients with CH, goiter and molecular diagnosis unknown. Samples of peripheral blood and thyroid tissue of patients and DNA samples from control subjects. Sequencing of the TPO gene, DUOX2 and DUOXA2. Analysis of gene expression of TPO, TG, NKX2.1, PDS, PAX8, NIS and TSHr by real time. Evaluation of the expression of luciferase under control of the promoter of TPO and TPO activity evaluation of the patients tissue. Results: The patients were identified change-95G> T homozygous, in the promoter region of TPO. We observed decrease in enzymatic activity of TPO in thyroid tissues of patients and decreased RNAm expression of this gene. Also found decreased expression of genes NKX2.1 and PAX8. Since the genes TG, TSHr, PDS, NIS mRNA expression presented increased. Functional analysis of the change -95G>T showed no descrease in reporter gene expression. Conclusion: The CH of patients due to decreased enzymatic activity of TPO, but changes were not found in the sequence of TPO gene to explain the decrease in activity. Epigenetic alterations in introns or in the TPO gene could explain the HC patients

O hipotireoidismo congênito, uma das alterações do metabolismo detectadas por meio da triagem neonatal, pode acarretar alterações no desenvolvimento global do indivíduo. O objetivo deste estudo foi traçar o perfil das habilidades do desenvolvimento em crianças com hipotireoidismo congênito e verificar possíveis influências dos dados da história clínica no perfil traçado. Foram avaliadas, por meio da Early Language Milestone Scale e do Inventário Portage Operacionalizado, 35 crianças (23 do gênero feminino e 12 do masculino) com hipotireoidismo congênito detectado pela triagem neonatal. As crianças pertenciam à faixa etária de 2 a 36 meses e realizavam tratamento com reposição hormonal há pelo menos um mês. Os dados da história clínica foram obtidos por meio de entrevista com os responsáveis legais pelas crianças e análise de prontuário. Na avaliação por meio da Early Language Milestone Scale, 11 crianças apresentaram desempenho alterado na função auditiva expressiva, 2 na função visual e 1 na função auditiva receptiva. Na avaliação por meio do Inventário Portage Operacionalizado, 7 crianças apresentaram desempenho alterado na área da linguagem, 5 na área cognitiva, 4 nas áreas motora e social e 3 na área de autocuidados. Não foram observadas influências dos dados da história clínica no resultado obtido. Concluiu-se que a maioria das crianças avaliadas neste estudo apresentou desempenho adequado para as habilidades avaliadas. Paras as crianças com desempenho alterado, observou-se maior déficit na área de linguagem, principalmente no que diz respeito aos aspectos expressivos e na área cognitiva. Não ficou provada a influência dos dados da história clínica no perfil traçado para as habilidades do desenvolvimento. Entretanto, observou-se tendência para desempenho adequado nas habilidades avaliadas entre as crianças que realizaram a triagem neonatal, receberam o diagnóstico e iniciaram o tratamento para o hipotireoidismo congênito mais precocemente e que receberam dosagem de levotiroxina mais elevada no início do tratamento. / The congenital hypothyroidism, one of the metabolism alterations detected through the neonatal screening, may cause alterations in the individual\'s global development. The objective of this study was to draw the profile of the development skills in children with congenital hypothyroidism and verify possible influences of the clinical history data in the drawn profile. It had assessed, through Early Languagem Milestone Scale and Inventário Portage Operacionalizado, 35 children (23 of the feminine gender and 12 of the masculine) with congenital hypothyroidism detected by the neonatal screening. The children belonged to the age group from 2 to 36 months and accomplished treatment with hormonal replacement for at least one month. The clinical history data were obtained through interview with the legal responsible for the children and handbooks analysis. In assessement through Early Languagem Milestone Scale, 11 children presented altered performance in auditory expressive function, 2 in visual function and 1 in auditory receptive function. In assessement through the Inventário Portage Operacionalizado, 7 children presented altered performance in the language area, 5 in cognitive area, 4 in motor and social areas and 3 in self-care area. Influences of the clinical history data were not observed in the obtained result. It was concluded that most of the assessed children in this study presented adequate performance for the evaluated skills. For the children with altered performance, larger deficit was observed in language area, mainly in expressive aspects and cognitive area. The influence of the clinical history data was not proven in the profile drawn for the development skills. However, tendency for appropriate performance in the assessed skills was observed among the children that accomplished the neonatal screening, received the diagnosis and began the treatment for the congenital hypothyroidism earlier and that received higher dose of thyroxine in the beginning of the treatment.