Introdução: O gene MAMLD1 tem sido relacionado à etiologia da hipospádia penoescrotal por ser fundamental para produção adequada de testosterona durante o período crítico do desenvolvimento sexual masculino. Até o momento, 3 mutações nonssense com perda de função foram identificadas em pacientes japoneses com hipospadia. Objetivo: Pesquisar a presença de mutações no gene MAMLD1, em uma grande casuística de pacientes brasileiros portadores de DDS 46,XY de origem indeterminada e realizar estudo funcional de possíveis alterações encontradas. Pacientes e Métodos: Avaliamos 50 pacientes com DDS 46.XY de causa indeterminada nos quais havia se excluído, previamente, os defeitos de síntese da testosterona, deficiência da 5 alfa-redutase 2 e insensibilidade parcial a andrógenos, por critérios laboratoriais e sequenciamento gênico. Toda região codificadora do MAMLD1 e os sítios de splice que flanqueiam essas regiões foram amplificados e sequenciados a partir do DNA genômico. Seis marcadores de microssatélites que flanqueiam o gene foram utilizados para analisar o efeito fundador da nova variante alélica identificada. A função de transativação do MAMLD1 foi analisada através de ensaio de luciferase. Células COS-1 foram distribuídas em placas de 12 poços e transitoriamente transfectadas com o vetor repórter de luciferase (p-Hes1, p-Hes3 e p-Hes5), vetor de expressão para MAMLD1 (selvagem e contendo a variante alélica) e o vetor PRL-CMV como um controle interno. Resultados: Identificamos uma variante alélica, a p.H347Q, no exon 3 em 4 pacientes brasileiros não relacionados (3 casos esporádicos e 1 caso familiar). Dois pacientes foram submetidos à gonadectomia na infância e foram criados no sexo social feminino. A ultrassonografia pélvica demonstrou a presença de útero em uma delas. Os outros dois pacientes do sexo masculino apresentavam micropênis, criptorquidia e hipospádia perineal. Esta variante alélica foi encontrada em apenas 1 de 250 controles brasileiros estudados frequência 0,4%. A atividade de transativação da variante protéica do MAMLD1 foi 2,0 vezes maior do que a proteína selvagem para ativar a transcriação do p-Hes3. Nenhum efeito fundador foi demonstrado nestas famílias. Discussão: A variante alélica está localizada em uma região altamente conservada do MAMDL1 que é essencial para o desenvolvimento da genitália masculina. Os genes Hes constituem uma família genes de repressor transcricional de sinalização intracelular Notch. Os genes Hes exibem um padrão de expressão oscilatório e controlam o momento exato de diversos eventos biológicos. O padrão de expressão dos genes Hes nas gônadas não é bem estabelecido. Hirata e col. demonstraram que tanto a ausência quanto a persistência da expressão dos genes Hes resultam nos mesmos defeitos na somitogênese. Nossa hipótese é que a superexpressão do gene Hes3 poderia prejudicar a diferenciação sexual masculina normal pela continua supressão de genes essenciais envolvidos posteriormente na cascata do desenvolvimento sexual masculino. Conclusão: Essa é a primeira descrição de uma variante alélica do gene MAMLD1 com ganho de função em pacientes com 46, XY DDS de causa indeterminada. O papel desta variante protéica do MAMDL1 na etiologia DDS 46,XY deve ser melhor determinada através de estudos in vivo / Introduction: MAMLD1 has been shown to be implicated in the etiology of penoscrotal hypospadias. To date, 3 loss-of-function nonsense mutations have been identified in Japanese patients with hypospadias. Objective: To screen MAMLD1 for mutations in a large cohort of Brazilian patients with undetermined 46,XY DSD. Patients and Methods: We evaluated 50 patients in which defects of testosterone synthesis, 5 alfa-reductase 2 deficiency and partial androgen insensitivity were previously excluded. The entire coding region and the flanking splicing sites of MAMLD1 were amplified and sequenced from genomic DNA. Six microsatellite markers flanking the gene were used to analyze founder effect of new allelic variant. Transactivation function of MAMLD1 was analyzed by a luciferase assays. COS-1 cells seeded in 12-well dishes were transiently transfected with luciferase reporter vector (p-Hes1, p-Hes3 and p-Hes5), expression vector for MAMLD1 (WT and allelic variant) and pRL-CMV vector as an internal control. All experiments were performed in triplicates and repeated 3 times. Results: We identified an allelic variant, the p.H347Q on exon 3 in 4 unrelated patients (3 sporadic and 1 familial cases). Two patients underwent gonadectomy in infancy and were raised as girls. Pelvic ultrasound showed a uterus in one of them. The other two male patients had micropenis, cryptorchidism and perineal hypospadias. This allelic variant was found in 1 out of 250 Brazilian controls frequency 0,4%. The transactivation activities of the variant protein were 2.0 folds higher than the WT with p-Hes3. No founder effect was demonstrated in these families. Discussion: The allelic variant is located in a highly conserved region of MAMDL1 which is essential for male genitalia development. HES is a family of transcriptional repressors of Notch signaling. Hes gene expression pattern is tissue and cell specific and control the timing of biological events. In gonads, their expression pattern remained to be elucidated. In somitogenesis, Hirata showed that both loss of expression or persistent expression of Hes genes result in the same defects. Therefore, overexpression of Hes genes should impair the normal male differentiation by continuous suppression of downstream genes involved in male sex development. Conclusion: This is the first report of an allelic variant of MAMLD1 determining a gain of function in its protein in patients with 46,XY DSD. The role of this variant protein of MAMDL1 in the etiology of 46, XY DDS should be better determined by in vivo studies

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Η τηλεϊατρική στηρίζεται στην εφαρμογή της σύγχρονης τεχνολογίας των τηλεπικοινωνιών,της πληροφορικής και τον ηλεκτρονικών υπολογιστών για παροχή υπηρεσιών υγείας, σε απομακρυσμένες περιοχές. Συνδυάζει δηλαδή την τεχνολογία με την ιατρική θέτοντας τις δυνατότητες της πρώτης στην διάθεση της δεύτερης. / The telemedicine is supported in the application of modern technology of telecommunications, information technology and computers for benefit of services of health, in removed regions. It combines that is to say the technology with the medicine placing the possibilities first in the disposal second.

Traditionally, working memory and its neural underpinnings have been studied in the visual domain. A rich and diverse amount of research has investigated the lateral prefrontal cortex (lPFC) as a primary area for visual working memory, while another line of research has found the neurotransmitter acetylcholine (ACh) to be involved. This dissertation used auditory cues and found similar patterns of activity for processing auditory working memory information within a task compared to visual working memory processes. The first two experimental chapters demonstrated that the cholinergic system is involved in auditory working memory in a comparable fashion to its role in visual working memory. In chapter 2, blocking ACh impaired performance on an auditory working memory task in a dose dependent manner. Chapter 3 investigated the specificity of the effect of blocking ACh by administering an ACh agonist (physostigmine) at the same time as an ACh antagonist (scopolamine). When both drugs were administered together performance on the delayed matching-to-sample task (DMTS) task improved compared to performance on scopolamine alone. These results support the hypothesis that ACh is involved in auditory working memory. Chapter 4 investigated the neural correlates of auditory working memory in area 46 and found that this region of the lPFC contains neurons that are responsive to auditory working memory components in a very similar way to how it this region encodes information during visual working memory tasks. Neurons in the lPFC are responsive to visual or auditory cues, the delay portion of tasks, the wait time (i.e. decision making period), response, and reward times. This type of coding provides support for the theories that position the lPFC as a key player in recognition and working memory regardless of modality.

It has recently been demonstrated that the presentation of a rare target in a visual oddball paradigm induces a prolonged inhibition of microsaccades. In the field of electrophysiology, the amplitude of the P300 component in event-related potentials (ERP) has been shown to be sensitive to the stimulus category (target vs. non target) of the eliciting stimulus, its overall probability, and the preceding stimulus sequence. In the present study we further specify the functional underpinnings of the prolonged microsaccadic inhibition in the visual oddball task, showing that the stimulus category, the frequency of a stimulus and the preceding stimulus sequence influence microsaccade rate. Furthermore, by co-recording ERPs and eye-movements, we were able to demonstrate that, despite being largely sensitive to the same experimental manipulation, the amplitude of P300 and the microsaccadic inhibition predict each other very weakly, and thus constitute two independent measures of the brain’s response to rare targets in the visual oddball paradigm.

This thesis analyzes the Christianisation process of the Roman Empire from the time of Constantine the Great to that of Justinian. The purposes of the ecumenical councils and the codes on the religious issues will be discussed in the framework of the religious policies of the emperors in that time. Between the time of Constantine and that of Justinian the Roman Empire became Christian Roman Empire. The Christianisation of the Roman Empire will be dealt with both from the religious and political point of view in this thesis.

Proefschrift--Godgeleerdheid--Nijmegen, 1979. / Bibliogr. p. 247-258. Index. Résumé en français.

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Submitted by Barroso Patrícia (barroso.p2010@gmail.com) on 2014-08-16T18:09:29Z No. of bitstreams: 1 MOTA, Bianca Costa.pdf: 1950610 bytes, checksum: cf1c3d3f181fbc2ecd92f0663fd6675c (MD5) / Made available in DSpace on 2014-08-16T18:09:29Z (GMT). No. of bitstreams: 1 MOTA, Bianca Costa.pdf: 1950610 bytes, checksum: cf1c3d3f181fbc2ecd92f0663fd6675c (MD5) / Introdução: O termo DDS refere-se aos distúrbios que afetam o processo normal de desenvolvimento e diferenciação sexual,os quais podem ou não se manifestar sob a forma de genitália ambígua,levando a discordância entre o sexo cromossômico, gonadal e fenotípico.A incidência estimada desses distúrbios é de umpara 4500-5500 nascimentos. Os indivíduos com DDS e cariótipo 46,XY apresentam virilização deficiente da genitália externa, que pode decorrer dehipoplasia das células de Leydig, alterações enzimáticas na síntese de testosterona, deficiência da enzima 5α-redutase, disgenesiasgonadais, anorquia, síndrome da insensibilidade androgênica ou DDS ovotesticular. Objetivo: Este trabalho teve como objetivo descrever o perfil clínico e epidemiológico de pacientes DDS 46,XY matriculados e acompanhados no Ambulatório de DDS do Hospital Universitário Professor Edgard Santos da Universidade Federal da Bahia. Metodologia: Trata-se de um estudo retrospectivo com revisão de prontuários dos pacientes com DDS 46,XY incluídos no banco de dados do referido ambulatório. Após análise desse banco de dados, foram selecionados todos os 122 pacientes com diagnóstico sindrômico de DDS 46,XY. Resultados: Foram estudados 110 pacientes; 47 deles não tinham diagnóstico etiológico; 16,apresentavam deficiência de 5α- redutase; 19, síndrome da insensibilidade androgênica. Na primeira consulta, a mediana da idade foi de 1,6 anos, 76 indivíduos eram do sexo masculino, 31 do sexo feminino e 03 ainda não tinham registro civil. Dois pacientes com registro civil feminino mudaram de gênero para o masculino durante o acompanhamento. Setenta e quatro pacientes foram encaminhados por apresentarem genitália ambígua ou criptorquidia. No grupo estudado, 73,6% tinham gônadas palpáveis.Entre os 47 pacientes sem diagnóstico etiológico, 87% foram registrados no sexo masculino. A gonadectomia e a uretoplastia foram as cirurgias mais realizadas, e 47% dos pacientes não realizaram qualquer tipo de cirurgia. Conclusão: As etiologias mais comuns foram: síndrome da insensibilidade androgênica (17%), deficiência de 5α-redutase (15%) e disgenesiasgonadais (6%). O diagnóstico etiológico não foi possível em 43% dos pacientes. A primeira avaliação ocorreu antes dos dez anos de idade em mais de 50% dos casos. Todos os pacientes com diagnóstico de síndrome da insensibilidade androgênica completa e 11 com deficiência de 5α-redutase foram registrados no gênero feminino. O motivo principal de encaminhamento foi a presença de ambiguidade genital. Todos os pacientes estudados estavam cadastrados no serviço de referência, e62% deles continuavam sendo acompanhados. O perfil clínico dos pacientes estudados está de acordo com os achados na literatura.

The Financial Accounting Standards Board (FASB) issued Interpretation No. 46 (FIN 46), Consolidation of Variable Interest Entities – An Interpretation of ARB No. 51, in January 2003 and revised it in December 2003, with the objective to improve the transparency of financial information. Under FIN 46, companies are required to consolidate variable interest entities (VIEs) on financial statements if they are the primary beneficiaries of the VIEs. This dissertation empirically examines whether the implementation of this new financial reporting guidance affects firms’ accruals quality and investment efficiency. A manually collected sample comprised of firms affected by FIN 46 and firms disclosing no material impact from FIN 46 is used in the empirical analyses.The first part of the dissertation investigates the effects of FIN 46 on accruals quality. By using different accrual quality measures in prior studies, this study found that firms affected by FIN 46 experienced a decrease in accrual quality compared to firms reporting no material impact from FIN 46. Among the firms affected by FIN 46, firms consolidating VIEs were compared with firms terminating or restructuring VIEs. The accruals quality of firms consolidating VIEs was found to be lower than that of firms terminating or restructuring VIEs. These results are consistent in tests using alternative control samples.The second part of this dissertation examines the effects of FIN 46 on investment efficiency. Mixed results were found from using two different proxies used in prior literature. Using the investment-cash flow sensitivity to proxy for investment efficiency, firms affected by FIN 46 experienced a decrease in investment efficiency compared to firms reporting no material impact. It was also found that higher investment-cash flow sensitivity for firms consolidating VIEs during post-FIN 46 periods compared to both the no-impact firms and the matched pair control sample. Contrasting results were found when the deviation from expected investment is used as another proxy for investment efficiency. Empirical analyses show that FIN 46 firms experienced improved investment efficiency measured by the deviation from expected investment after their adoption of FIN 46. This study also provides explanations for the opposite results from the two different proxies.