Avec l'avènement des systèmes intégrés complexes, la vérification par assertions(Assertion Based Verification ou ABV) s'est imposée comme une solution pour la vérification semi-formelle des circuits. L'ABV permet de valider qu'un circuit satisfait ou non une propriété(ou assertion). Des travaux antérieurs ont montré qu'il était possible de synthétiser ces propriétés sous la forme de moniteurs matériels. Ces derniers peuvent ainsi être embarqués à demeure sur un circuit afin qu'ils assurent une tâche de monitoring. Avec un objectif de surveillance et de sûreté, l'utilisation de tels moniteurs est un plus. Néanmoins, ces derniers sont aussi sensibles que les circuits surveillés à une dégradation environnementale(tension, température, vieillissement, …). Afin de réduire le risque de dysfonctionnement des moniteurs, initialement conçus comme des circuits synchrones, une variante asynchrone(quasi-insensible aux délais) est proposée dans cette thèse. Ces travaux s'inscrivent dans le cadre du projet ANR SFINCS(Thalès, Dolphin Integration, TIMA) et ont mené à la définition d'une méthode de synthèse de moniteurs asynchrones matériels tirant parti de la robustesse et de la modularité des implémentations asynchrones. Les études menées se focalisent en premier lieu sur la conception d'une bibliothèque de moniteurs élémentaires asynchrones et sur une méthode d'interconnexion ad hoc permettant de constituer des moniteurs complexes. Afin de garantir les bonnes propriétés de robustesse de ces moniteurs, une étude a été menée à l'aide de l'outil de vérification formelle RAT. Il a notamment été prouvé que la connexion d'un moniteur asynchrone avec un circuit synchrone(à surveiller) était un point particulièrement délicat car les hypothèses du circuit synchrone contraignent le moniteur asynchrone. Il a donc été proposé d'introduire un dispositif de contrôle de l'horloge du circuit synchrone, appelé « clock stretching », afin de relaxer les hypothèses temporelles synchrones qui sont appliquées à la partie asynchrone. / With the advent of complex integrated systems, the assertion based verification(ABV) has emerged as a solution for the semi-formal circuits verification. The ABV is used to validate that a circuit satisfies a property(or assertion). Previous work has shown that it is possible to synthesize these properties in the form of hardware monitors. These can then be embeddded permanantly on a circuit so that they provide monitoring task. With a goal of security and surveillance, the use of such monitors is a plus. Nevertheless, they are as sensitive as the monitored circuits to environmental degradation(voltage, temperature, age, ...). To reduce the risk of failure in monitors, originally designed as synchronous circuits, an asynchronous variant(quasi-delay insensitive) is proposed in this thesis. This work is part of the ANR project SFINCS(Thales, Dolphin Integration, TIMA) and led to the definition of a method for synthesizing asynchronous hardware monitors leveraging the robustness and modularity of asynchronous implementations. The studies focus primarily on the design of a library of basic asynchronous monitors and an ad hoc method of interconnection to build complex monitors. To ensure the robustness of these monitors, a study was conducted using formal verification tool RAT. In particular it was proved that the connection of an asynchronous monitor with a synchronous circuit(to watch) was particularly tricky because the timing assumptions of synchronous circuit impact the asynchronous monitor. It was therefore proposed to introduce a devicet, called "clock stretching", for controlling the clock of the synchronous circuit and relax synchronous timing assumptions that are applied to the asynchronous monitor.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Idiopathic Short Stature is a heterogeneous set of conditions without obvious hormonal changes or defined etiologies. It may include the partial insensitivity to GH (PGHI) and the moderate GH deficiency (MGHD), both of them with low concentrations of growth factor like insulin type I (IGF-I) and hyper or sub-answer of GH on tests of stimulation, respectively. The objective of this study is to assess the response to treatment with GH in PGHI and MGHD, comparing them twith the results obtained in a group with severe GH deficiency (SGHD). It was studied in PGHI (GH peak ≥18 ng/ml) 20 individuals (14 boys), 12.07 (2.57-year-old); in MGHD (GH peak between 5 and 10 ng/ml) 12 (7 boys), 10.73 (1.79-year-old); and in SGHD (GH peak lower than 5 ng/ml) 19 (10 boys), 10.90-(3.51) yearold, treated with GH for one to ten years. The initial and present GH doses were, respectively, 43.33(10.00) and 49.61 (12.90) μg/kg/day in SGHD, 50.27 (11.76) and 57.27 (15.83) μg/kg/day in MGHD; and50.18 (6.99) and 55.66 (9.61) μg/kg/day in PGHI. The standard deviation score (SDS) of initial height of the SGHD group was lower than MGHD group (p< 0.01) and PGHI group (p <0.001).The SDS of initial IGF-I of SGHD was similar to MGHD and lower than PGHI group (p<0.0001).The initial bone age (BA) in SGHD group was similar to MGHD and lower than PGHI group GH (p < 0.01). GH treatment has brought about a lower increase in the height SSD and in the IGF-I SSD (both, p < 0.05) and in the bone age (p< 0.01) in the PGHI group than in the SGHD group, probably due to the more accentuated height deficit in the SGHD group and lower IGF-I increase in the PGHI group. Treatment response was similar in MGHD and SGHD groups. The lowest height gain in the PGHI suggests that the partial GH insensitivity needs higher GH doses to be effective. / A baixa estatura idiopática é um conjunto heterogêneo de condições sem evidentes alterações hormonais ou etiologias definidas. Pode incluir a insensibilidade parcial ao GH (IPGH) e a deficiência moderada de GH (DMGH), ambas com concentrações baixas de fator de crescimento semelhante à insulina tipo I (IGF-I) e hiper ou sub-resposta do GH aos testes de estímulo, respectivamente. O objetivo do presente trabalho é avaliar a resposta ao tratamento com GH na IPGH e DMGH, comparando-as com os resultados obtidos na deficiência grave de GH (DGGH). Foram estudados no grupo IPGH (pico de GH ≥18 ng/ml), 20 indivíduos (14 meninos), com 12,0 (2,57) anos de idade; no grupo DMGH (pico de GH entre 5 e 10 ng/ml), 12 (sete meninos), com 10,73 (1,79) anos; e no DGGH (pico de GH < 5 ng/ml), 19 (10 meninos), com 10,90 (3,51) anos, tratados com GH por um a dez anos. As doses de GH iniciais e atuais foram, respectivamente, 43,33 (10,00) e 49,61 (12,90) μg/kg/dia no DGGH; 50,27 (11,76) e 57,27 (15,83) μg/kg/dia no DMGH; e 50,18 (6,99) e 55,66 (9,61) μg/kg/dia no IPGH. O escore de desvio-padrão (EDP) da altura inicial do grupo DGGH foi menor do que no DMGH (p< 0,01) e no IPGH (p <0, 001). O EDP do IGF-I inicial do grupo DGGH foi similar ao DMGH e menor do que o do IPGH (p< 0, 0001). A idade óssea inicial no grupo DGGH foi similar ao DMGH e menor do que a do grupo IPGH (p < 0,01). O tratamento com GH propiciou um menor incremento no EDP da altura e no EDP do IGF-I (ambos, p < 0,05) e na IO (p< 0,01) no grupo IPGH do que no DGGH, provavelmente refletindo o maior déficit estatural no grupo com DGGH e menor aumento do IGF-I no grupo IPGH. A resposta ao tratamento nos grupos DMGH e DGGH foi semelhante. O ganho estatural menor no grupo IPGH sugere que a insensibilidade parcial ao GH necessitaria de doses mais altas de GH para ser vencida.

Made available in DSpace on 2014-07-29T15:16:33Z (GMT). No. of bitstreams: 1 dissertacao wyara biologia.pdf: 1287742 bytes, checksum: 4b2f592f2b219248664d4916820cd874 (MD5) Previous issue date: 2009-03-31 / Male idiopathic infertility is related to defects in normal spermatogenesis, due to genetic causes. The spermatogenesis is a dependent process on high levels of male sex hormones, the androgens. The androgen, in turn, perform its function when associated with the androgen receptor (AR), protein encoded by AR gene. Mutation in AR gene lead to a synthesis of non functional AR, which results in the failure of the process of spermatogenesis and, consequently, causes male infertility. This work has as its main objective the verification of the occurrence of mutation in the AR gene in patients with male idiopathic infertility who come from the HC-UFG Human Reproduction Center. Samples were analyzed from 206 patients. The result was that 95 patients were found to be normal while 111 with an altered result for the spermogram. The samples were amplified for exons 1, 4, 6, 7 and 8 of the AR gene and the results subjected to statistical analysis, Mann Whitney, logistic regression, and chi tests. The existence of the relationship between defects of sperm and AR gene mutation was verified. The analysis of the relationship between the spermogram and the AR gene mutation in five evaluated exons was significant only for exons 1 and 7. Patients with numerical unsettled spermogram had a higher frequency of mutations in exon 7, teratozoospermics in exon 1 and exon 7 in astenozoospermics patients. Exons 4, 6 and 8 showed no meaningful statistical relationship in reference to the alteration of the spermogram. Among results related to social custom, alcohol proved to be significant for mutation in the AR gene. This study has reaffirmed the relationship between the presence of mutation in AR genes as probable causes of defects in spermatogenesis. Consequently, male idiopathic infertility depends not only on the genetic factor, but also on the association between this factor and the environment where man inhabits / A infertilidade masculina idiopática está relacionada a defeitos na espermatogênese normal, devido a causas genéticas. A espermatogênese é um processo dependente de altos níveis de hormônios sexuais masculinos, os andrógenos. E os andrógenos, por sua vez, exercem sua função quando associados ao receptor androgênico (RA), proteína codificada pelo gene RA. Mutações no gene RA levam a síntese do RA não funcional, o que acarreta em falhas no processo de espermatogênese e consequentemente causam infertilidade masculina. O trabalho teve como principal objetivo verificar a ocorrência ou não de mutação no gene RA em pacientes com infertilidade masculina idiopática do Centro de Reprodução Humana do HCUFG. Foram analisadas 206 amostras de pacientes, sendo 95 normais e 111 alterados para o espermograma. As amostras foram amplificadas para os exons 1, 4, 6, 7 e 8 do gene RA e os resultados submetidos às análises estatísticas, teste U, quiquadrado e regressão logística. Foi verificada a existência de relação entre alteração no espermograma e mutação no gene RA. A análise da relação entre espermograma e mutação no gene RA dos cinco exons avaliados foi significativa somente para os exons 1 e 7. Os pacientes com alteração numérica para o espermograma apresentaram uma freqüência maior de mutações no exon 7, os pacientes teratozoospérmicos no exon 1 e os astenozoospérmicos no exon 7. Os exons 4, 6 e 8 não apresentaram relação estatística significativa para alterações no espermograma. Dentre os resultados referentes aos hábitos sociais, o etilismo mostrou-se significativo para mutações no gene RA. A realização desse estudo vem reafirmar a relação entre presença de mutações no gene RA como prováveis causas de defeitos na espermatogênese e, consequentemente, infertilidade masculina idiopática, não dependendo exclusivamente do fator gênico, mas da associação entre este fator e o meio ambiente onde o homem está inserido

Abstract Glucocorticoids are the most important and widely used treatment modality in dermatology. A large variety of topical as well as systemic preparations is available. Most patients treated with glucocorticoids respond quickly to the treatment, but some are considered insensitive or even resistant to glucocorticoid therapy. Currently, there is no known measurable variable, through which the response can be predicted. Glucocorticoids mediate their actions through glucocorticoid receptors (GR). Several isoforms of GR exist, but the α (GRα) and β (GRβ) isoforms are clinically the most important. Based on previous studies, it has been proposed that the abundance of GR isoforms or the GRβ: GRα –ratio could affect individual responsiveness to corticosteroid treatment. In particular, up-regulation of GRβ expression has been shown to be linked to resistance to corticosteroid treatment. This thesis comprises three sub-studies. Firstly, we wanted to determine whether GRα and GRβ are expressed in inflammatory skin diseases. Secondly, we examined if the expression is altered by corticosteroid treatment in eczema atopicum, bullous pemphigoid and psoriasis. Finally, we measured the effects of a topical vitamin D3 analogue (calcipotriol) combined with betamethasone compared with betamethasone monotherapy on inflammatory biomarkers of psoriasis. Our studies provide detailed novel data about the expression of GRα and GRβ. GRα and GRβ were shown to be expressed in the blood lymphocytes and lesional skin of patients with eczema atopicum, bullous pemphigoid and psoriasis, as well as in the skin of patients with eczema nummulare, lichen simplex chronicus and lichen ruber planus. Systemic corticosteroid treatment was shown to affect the expression of GRα and GRβ in eczema atopicum and bullous pemphigoid, but the inconsistent variation in their expression between patients prevented us from drawing firm conclusions. Neither GRα nor GRβ as a single marker were found to be a suitable predictor of corticosteroid responsiveness. Clinical and laboratory analyses showed that topical treatment of psoriasis with calcipotriol/betamethasone combination ointment is more beneficial measured by both than betamethasone monotherapy. / Tiivistelmä Glukokortikoideja (”kortisoni”) käytetään tulehduksellisten ihotautien hoidossa paikallisesti tai systeemisenä lääkkeenä. Suurin osa potilaista reagoi hoitoon nopeasti, mutta osalla hoitovaste on heikompi tai ilmenee hitaasti. Tällä hetkellä ei tunneta keinoja ennustaa luotettavasti kortisonihoidon vastetta. Glukokortikoidit vaikuttavat elimistössä glukokortikoidireseptorien (GR) kautta. Glukokortikoidireseptorista tunnetaan useita alatyyppejä, joista tärkeimmät ovat α (GRα) ja β (GRβ). Aiemman tiedon pohjalta on pidetty mahdollisena, että GR-alatyyppien suhteella tai määrällä on merkitystä kortisonivasteen syntymisessä. Erityisesti on arveltu, että ylimäärä GRβ:aa voisi estää kortisonihoidon vaikutusta. Tässä väitöskirjassa tavoitteena on ollut selvittää, tapahtuuko GR-alatyyppien ilmenemisessä muutoksia tulehduksellisia ihosairauksia sairastavilla potilailla sekä tutkia, miten kortisonihoito vaikuttaa GR-tasoihin atooppista ihottumaa, pemfigoidia ja psoriaasia sairastavilla potilailla. Lisäksi olemme verranneet paikallishoitoa pelkällä kortisonivoiteella D-vitamiinijohdos kalsipotriolin ja kortisonin yhdistelmähoitoon psoriaatikoilla. Tutkimus on antanut uutta yksityiskohtaista tietoa GRα:n ja GRβ:n esiintymisestä ihossa ja tulehdussoluissa ihosairauksia sairastavilla potilailla. Tutkimustulosten perusteella voidaan todeta, että GRα ja GRβ esiintyvät atooppista ihottumaa, pemfigoidia ja psoriaasia sairastavien potilaiden ihossa ja veren tulehdussoluissa sekä nummulaari-ihottumaa, neurodermatiittia ja punajäkälää sairastavien potilaiden ihossa. Suun kautta annettu kortisonihoito vaikuttaa GRα- ja GRβ–lähetti-RNA:n ilmenemiseen, mutta potilaskohtaiset erot ovat suuret, eikä kumpikaan, GRα tai GRβ, sovellu yksinään ennustamaan kortisonihoidon vastetta. Paikallisella kortisonihoidolla D-vitamiinijohdos kalsipotrioliin yhdistettynä on suotuisampi vaikutus psoriaasin tulehduksellisiin välittäjäaineisiin ja tulehdussoluihin kuin pelkällä paikallisella kortisonihoidolla.