Nos casos de hiperparatireoidismo secundário onde não é possível o tratamento clínico, é indicada a paratireoidectomia. No Serviço de Cirurgia de Cabeça e Pescoço do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, o tipo de cirurgia utilizada é a paratireoidectomia total com auto-implante de paratireóide em membro superior. Nesses casos, ao contrário da paratireoidectomia total, pode haver recidiva do hiperparatireoidismo no sítio do implante, com sintomas sistêmicos e com necessidade de intervenção para retirada do tecido hiperplásico. Já na paratireoidectomia total, há hipoparatireoidismo definitivo e risco de doença óssea adinâmica. O presente estudo tem como escopo avaliar os pacientes submetidos a paratireoidectomia com implante e esclarecer se há fatores clínicos e de imunohistoquímica que possam indicar antes da cirurgia algum risco de recidiva no implante / When clinical treatment of secondary hyperparathyroidism fails, parathyroidectomy is mandatory. Total parathyroidectomy and immediate parathyroid autotransplantation in the forearm is the treatment of choice at Head and Neck Surgery of Hospital das Clínicas of University of São Paulo Medical School. In this cases, recurrent hyperparathyroidism may be caused by hyperplastic graft tissue. Without autotransplantation, adinamic bone disease may occur. The present study seek to evaluate patients submitted to total parathyroidectomy and autotransplantation and try to clarify clinical or immunohistochemical

Introdução: O seguimento de pacientes com câncer de bexiga superficial apresenta embargos financeiros e psicológicos ao paciente, devido à realização frequente de exames invasivos. Com fim de substituir ou diminuir os exames invasivos, busca-se biomarcadores urinários acurados, que permitam diagnosticar a recidiva tumoral e estratificar pacientes com maior risco de recidiva futura. O objetivo deste estudo é avaliar se expressão na urina de PAI-1, DJ-1, ApoA-1, MMP-9 e IL-8 permite identificar e antecipar a recidiva de câncer de bexiga. Método: A expressão da PAI-1, DJ-1, ApoA-1, MMP-9 e IL-8 foi mensurada por ELISA na urina de 152 pacientes tratados previamente de carcinoma urotelial superficial de bexiga e em seguimento. Os níveis das proteínas foram comparados entre pacientes com e sem recidiva de câncer de bexiga (1) no momento da coleta de urina e (2) durante o seguimento. A ocorrência de recidiva tumoral foi confirmada por análise histopatológica da biópsia de lesões suspeitas, investigadas quando havia alterações na cistoscopia, ultrassom ou citologia oncótica. Pacientes com recidiva diagnosticada no momento da coleta de urina foram excluídos da análise para avaliar o papel antecipatório das cinco proteínas. Foi avaliado se o uso prévio de BCG intra-vesical exercia influência no nível das cinco proteínas estudadas. Resultados: Entre os pacientes avaliados, 16 (10,5%) apresentaram recidiva de carcinoma urotelial no momento da coleta de urina e 21 (15,4%) apresentaram recidiva de carcinoma urotelial durante o seguimento. O seguimento mediano foi de 47 meses (interquartis de 39 e 50 meses). Um painel para o diagnóstico de recidiva tumoral incluindo três biomarcadores (ApoA-1, MMP-9 e IL-8) apresentou razão de risco de 12,9 (IC 95% =3,5-47,4) e um painel para prever pacientes que desenvolverão recidiva durante o seguimento incluindo dois biomarcadores (PAI-1 e IL-8) apresentou razão de risco de 4,1 (IC 95% =1,4-11,4). Os resultados dos painéis não foram influenciados pelo uso prévio de BCG intra-vesical. Conclusão: Os painéis apresentados permitem identificar pacientes com recidiva de carcinoma urotelial de bexiga e prever quais pacientes terão maior risco de desenvolver recidiva no futuro. O uso prévio de BCG intra-vesical não alterou a expressão dos biomarcadores / Purpose: To evaluate if the urinary levels of PAI-1, DJ-1, ApoA-1, MMP-9 and IL-8 can identify and predict tumor recurrence in patients on follow-up of superficial bladder cancer. Methods: We prospectively analyzed the urine of 152 patients previously treated of superficial bladder cancer on follow-up regimen. Five biomarkers (PAI-1, DJ-1, ApoA-1, MMP-9 and IL-8) were assessed by ELISA and compared among patients with and without bladder cancer recurrence (1) in the moment of urine collection and (2) during follow-up. Tumor recurrence was evaluated with cystoscopy, ultrasound and urine oncotic cytology and confirmed by pathological analysis. Patients with recurrence at urine collection were excluded from prediction analysis. A correlation between the level of the biomarkers and previous use of intravesical BCG was investigated. Results: Median follow-up was 47 months (IQR =39-50 months). Among patients included, 16 (10,5%; N =152) and 21 (15,4%; N =136) had bladder cancer recurrence diagnosed in the moment of urine collection and during follow-up, respectively. The panel to diagnose recurrence including 3 biomarkers (ApoA-1, MMP-9 and IL-8) presented OR =12,9 (CI =3,5-47,4), while the panel to predict patients who will have a recurrence during follow-up including 2 biomarkers (PAI-1 and IL-8) presented OR =4,1 (CI =1,4- 11,4). Previous use of intra-vesical BCG didn\'t influence urine biomarkers expression. Conclusions: The 3-biomarker panel can be used to identify patients with bladder cancer recurrence. The 2-biomarker panel can be used to predict patients at greater risk of bladder cancer recurrence during follow-up. Both are reliable in patients with previous use of intravesical BCG

Vom Standpunkt des Physikers aus gesehen, ist die Erde ein dynamisches System von großer Komplexität. Funktionale Netzwerke werden aus Beobachtungs-, und Modelldaten abgeleitet oder aufgrund theoretischer Überlegungen konstruiert. Indem sie statistische Zusammenhänge oder kausale Wirkbeziehungen zwischen der Dynamik gewisser Objekte, z.B. verschiedenen Sphären des Erdsystems, Prozessen oder lokalen Feldvariablen darstellen, bieten funktionale Netzwerke einen natürlichen Ansatz zur Bearbeitung fundamentaler Probleme der Erdsystemanalyse. Dazu gehören Fragen nach dominanten, dynamischen Mustern, Telekonnektionen und Rückkopplungsschleifen in der planetaren Maschinerie, sowie nach kritischen Elementen wie Schwellwerten, sogn. Flaschenhälsen und Schaltern im Erdsystem. Der erste Teil dieser Dissertation behandelt die Theorie komplexer Netzwerke und die netzwerkbasierte Zeitreihenanalyse. Die Beiträge zur Theorie komplexer Netzwerke beinhalten Maße und Modelle zur Analyse der Topologie (i) von Netzwerken wechselwirkender Netzwerke und (ii) Netzwerken mit ungleichen Knotengewichten, sowie (iii) eine analytische Theorie zur Beschreibung von räumlichen Netzwerken. Zur Zeitreihenanalyse werden (i) Rekurrenznetzwerke als eine theoretisch gut begründete, nichtlineare Methode zum Studium multivariater Zeitreihen vorgestellt. (ii) Gekoppelte Klimanetzwerke werden als ein exploratives Werkzeug der Datenanalyse zur quantitativen Charakterisierung der komplexen statistischen Interdependenzstruktur innerhalb und zwischen distinkten Feldern von Zeitreihen eingeführt. Im zweiten Teil der Arbeit werden Anwendungen zur Detektion von dynamischen Übergängen (Kipppunkten) in Zeitreihen, sowie zum Studium von Flaschenhälsen in der atmosphärischen Zirkulationsstruktur vorgestellt. Die Analyse von Paläoklimadaten deutet auf mögliche Zusammenhänge zwischen großskaligen Veränderungen der afrikanischen Klimadynamik während des Plio-Pleistozäns und Ereignissen in der Menschheitsevolution hin. / The Earth, as viewed from a physicist''s perspective, is a dynamical system of great complexity. Functional complex networks are inferred from observational data and model runs or constructed on the basis of theoretical considerations. Representing statistical interdependencies or causal interactions between objects (e.g., Earth system subdomains, processes, or local field variables), functional complex networks are conceptually well-suited for naturally addressing some of the fundamental questions of Earth system analysis concerning, among others, major dynamical patterns, teleconnections, and feedback loops in the planetary machinery, as well as critical elements such as thresholds, bottlenecks, and switches. The first part of this thesis concerns complex network theory and network-based time series analysis. Regarding complex network theory, the novel contributions include consistent frameworks for analyzing the topology of (i) general networks of interacting networks and (ii) networks with vertices of heterogeneously distributed weights, as well as (iii) an analytical theory for describing spatial networks. In the realm of time series analysis, (i) recurrence network analysis is put forward as a theoretically founded, nonlinear technique for the study of single, but possibly multivariate time series. (ii) Coupled climate networks are introduced as an exploratory tool of data analysis for quantitatively characterizing the intricate statistical interdependency structure within and between several fields of time series. The second part presents applications for detecting dynamical transitions (tipping points) in time series and studying bottlenecks in the atmosphere''s general circulation structure. The analysis of paleoclimate data reveals a possible influence of large-scale shifts in Plio-Pleistocene African climate variability on events in human evolution.

La contribution relative des différentes entrées sensorielles dans le contrôle postural a souvent été étudiée dans le cadre de la posture érigée fondamentale. L’objectif de nos travaux a été de déterminer cette contribution dans deux postures relativement proches dans leur configuration : l’appui tendu renversé (ATR) et la verticale inversée (VI) en milieu aquatique. Si la vision est souvent considérée comme information principale dans le contrôle postural de la station érigée, la configuration structurelle (champ visuel restreint en ATR, immersion de l’œil en VI) de ces deux postures laisse imaginer un fonctionnement différent. La perturbation des différents capteurs sensoriels impliqués dans le contrôle postural a permis d’observer la réorganisation mise en place par le système nerveux central (SNC) pour y remédier. De plus la prise en compte d’un facteur perceptif comme la dépendance au champ visuel nous a paru être un élément pertinent pour tenter d’observer d’éventuelles différences interindividuelles dans les comportements des sujets. La perturbation du contrôle postural a été évaluée au travers d’une analyse cinématique et d’une analyse stabilométrique de l’ATR (analyse classique et non-linéaire). Les résultats de ces analyses laissent entrevoir des différences de stratégie entre les sujets dépendants et indépendants au champ visuel dans le contrôle de l’appui tendu renversé, ce qui ne semble pas être le cas en verticale inversée / The relative contribution of the different sensory inputs in erect postural control has often been studied. The aim of this work is to determine this contribution in two positions relatively close in their configuration: the handstand and the upside-down posture in water. If vision is often considered as the main information in postural control, the structural configuration (restricted visual field in handstand, eye’s immersion in upside-down posture) of these two postures lets imagine a different operation. Disruption of sensory receptors involved in postural control has allowed observing the reorganization implemented by the central nervous system (CNS). In addition, the visual field dependence appeared to be a relevant factor to observe interindividual behavioral differences. Disturbance of postural control was assessed through a kinematic analysis and a stabilometric analysis of the handstand (classical analysis and non-linear analysis). Results of these analyzes suggest different strategy according to visual field dependence in the control of the handstand, which does not seem to be the case in upside-down posture

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Roman&quot;,&quot;serif&quot;;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;color:black;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Karcinom dojke je heterogena bolest koju karakteri&scaron;u različita morfologija, imunohisto-hemijski profil, klinički tok i terapijski odgovor. Ki-67 proliferativni indeks je jedan od markera sa prognostičkim i prediktivnim značajem, čije metodolo&scaron;ko određivanje i analiza jo&scaron; uvek nisu standardizovani. <b>Cilj: </b>Utvrditi graničnu (&ldquo;cut-off&rdquo;) prognostičku vrednost Ki-67 indeksa, kao i povezanost vrednosti Ki-67 u ranom luminalnom karcinomu dojke sa prognostičkim i prediktivnim parametrima karcinoma dojke, kao &scaron;to su životna dob bolesnica, veličina tumora, histolo&scaron;ki gradus (HG) i nivo tumorske ekspresije receptora estrogena (ER) i progesterona (PR). Takođe, cilj istraživanja je i utvrđivanje značajnosti razlike u vrednosti Ki-67 proliferativnog indeksa u odnosu na pojavu lokalnog recidiva, udaljenih metastaza i dužinu preživljavanja u toku petogodi&scaron;njeg perioda praćenja pacijentkinja. <b>Metode: </b>Retrospektivno je analizirano 120 patohistolo&scaron;kih izve&scaron;taja bolesnica kojima je u periodu od 01.01.2009. godine do 31.12.2011. godine na Institutu za onkologiju Vojvodine imunohistohemijskom analizom dokazan luminalni karcinom dojke (pozitivan ER i PR, negativan HER2), bez metastaza u aksilarnim limfnim čvorovima. <b>Rezultati: </b>Metodama deskriptivne statistike prosečna starost pacijentkinja je iznosila 57,42&plusmn;10,17 godina; prosečna veličina tumora 17,98&plusmn;6,97mm; recidiv je registrovan kod 8 (6,7%) pacijentkinja uz prosečan vremenski period do pojave recidiva od 49&plusmn;20,23 meseci. Vrednost &ldquo;cut off&rdquo; indeksa Ki-67 od prognostičkog značaja za vremenski period bez recidiva je iznosio 20,75%. Nije dokazana signifikantna veza između vrednosti Ki-67 i godina starosti pacijentkinja (p=0,401, odnosno p=0,293), kao i jačine ekspresije ER (p=1,00, p=0,957) i PR (p=0,273, p=0,189). Ustanovljena je signifikantna povezanost Ki-67 postoji sa veličinom (p=0,035, p=0,20) i HG tumora (p=0,041, p=0,20). Prosečan period praćenja bolesnica iznosio je 72,92&plusmn;8,38 meseci; nije registrovana pojava udaljenih metastaza, kao ni smrtni ishod. U odnosu na pojavu lokalnog recidiva, Kaplan-Majerovom analizom i Koksovom regresionom analizom proliferativni indeks Ki-67 se pokazao kao signifikantan prediktor za procenu ponovnog javljanja bolesti, lokalnog recidiva (Log rank (df = 1) = 2,73; p=0,045). Takođe je ustanovljeno da je statistički značajan prediktor za procenu recidiva bolesti i starosna dob bolesnica (Log rank (df = 1) = 6,885; p=0,009). Intenzitet pozitivnosti ER i PR, veličina tumora i histolo&scaron;ki gradus se nisu pokazali kao prediktori za pojavu recidiva luminalnih karcinoma dojke (p &gt; 0,05). <b>Zaključak: </b>Zbog heterogene prirode oboljenja, kori&scaron;ćenjem standardnih histopatolo&scaron;kih faktora i biomarkera te&scaron;ko je predvideti tok i ishod karcinoma dojke. Ki-67 je proliferativni marker, čija visoka vrednost korelira sa faktorima lo&scaron;e prognoze.</span></p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>Tanja Lakic</o:Author> <o:Version>12.00</o:Version> </o:DocumentProperties></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> <w:UseAsianBreakRules/> <w:DontGrowAutofit/> <w:SplitPgBreakAndParaMark/> <w:DontVertAlignCellWithSp/> <w:DontBreakConstrainedForcedTables/> 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Normal";mso-tstyle-rowband-size:0;mso-tstyle-colband-size:0;mso-style-noshow:yes;mso-style-priority:99;mso-style-qformat:yes;mso-style-parent:"";mso-padding-alt:0cm 5.4pt 0cm 5.4pt;mso-para-margin-top:0cm;mso-para-margin-right:0cm;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]--></p><p class="Default"><b><span style="font-size:11.0pt">Introduction: </span></b><span style="font-size:11.0pt">Breast cancer is a heterogeneous disease characterized by different morphology, immunohistochemical profile, clinical course and response to applied therapy. Ki-67 proliferative index is one of the prognostic and predictive factors, whose methodological determination and analysis are still unstandardized. <b>Objective: </b>Determination of cut-off value for Ki-67 index, its corelation in luminal breast carcinoma with patient&#39;s age, tumor size, histological grade (HG) and expression of estrogen (ER) and progesterone (PR). Also, the aim of the study was to determine the significance of the difference in the value of the Ki-67 proliferative index in relation to the occurrence of local relapse, distant metastases and survival rates during the five-year follow-up period of the patient. <b>Methods: </b>Retrospectively, we analysed 120 pathohistological reports of patients who were treated in the period from 01.01.2009 until 31.12.2011 at the Oncology Institute of Vojvodina, and to whom immunohistochemically was proven luminal breast cancer (positive ER and PR, negative HER2), without axillary lymph node metastases. </span><b><span style="font-size:11.0pt">Results: </span></b><span style="font-size:11.0pt">The average patient&rsquo;s age was 57.42&plusmn;10.17 years; average tumor size 17.98&plusmn;6.97mm; recurrence was registered in 8 (6.7%) patients with average recurrence time of 49&plusmn;20.23 months. &quot;Cut off&quot; Ki-67 value of prognostic significance for period without recurrence was 20.75%. Test didn&rsquo;t show significant relationship between Ki-67 and patient&rsquo;s age (p=0.401 and p=0.293), as well as the strength of expression ER (p=1.00, p=0.957) and PR (p=0.273, p=0.189). Significant correlation was present for Ki-67 with size (p=0.035, p=0.20) and tumor&rsquo;s HG (p=0.041, p=0.20). The average follow-up period for patients was 72.92&plusmn;8.38 months; there was no registered occurrence of distant metastases or fatal outcome. In relation to the occurrence of local relapse, Kaplan-Meier analysis and Cox regression analysis, the proliferative index Ki-67 proved to be a significant predictor for the assessment of recurrence of the disease, local relapse (Log rank (df = 1) = 2.73; p = 0.045). Also, it was founded that a statistically significant predictor for assessing the recurrence of the disease is the age of the patients (Log rank (df = 1) = 6.885; p = 0.009). The intensity of ER and PR expression, tumor size and histological grade have not been shown to be predictors of the recurrence of luminal breast carcinoma (p&gt; 0.05). </span><b><span style="font-size:11.0pt">Conclusion: </span></b><span style="font-size:11.0pt">Breast carcinoma is heterogeneous disease, so it is difficult to predict its course and outcome using standard histopathological factors and biomarkers. Ki-67 is proliferative marker whose high value correlates with factors of bad prognosis. </span></p>

Introdução: Os mecanismos envolvidos na patogênese molecular dos tumores hipofisários corticotróficos são complexos, heterogêneos e permanecem na maioria dos casos desconhecidos. Alterações da expressão de componentes da via Ikaros (Ik), tais como do receptor 4 dos fatores de crescimento de fibroblastos (FGFR4) têm sido detectadas em tumores hipofisários, inclusive nos corticotropinomas. O desbalanço entre as isoformas longas e curtas do Ikaros resulta em um início de transcrição alternativa do FGFR4, codificando uma isoforma truncada do gene (pdt- FGFR4) que foi associada a tumores hipofisários maiores e mais invasivos. A isoforma curta Ik6 promove a expressão do fator anti-apoptótico Bcl-XL in vitro, um efeito independente da interação com as isoformas longas. Além disso, um polimorfismo do FGFR4, com substituição da glicina por arginina no códon 388 (G388R), tem sido associado à evolução desfavorável em vários tipos tumorais humanos. Objetivos: Analisar a expressão do Bcl-XL, das isoformas do Ikaros (Ik1+Ik2/Ik total) e do FGFR4 em corticotropinomas humanos. Avaliar a freqüência dos genótipos do códon 388 do FGFR4 nos pacientes com doença de Cushing e sua associação com a evolução pósoperatória após a primeira cirurgia transesfenoidal. Métodos: Noventa e sete pacientes com diagnóstico de doença de Cushing foram estudados. Os dados clínicos, hormonais e histopatológicos foram avaliados retrospectivamente. O estudo da expressão do Bcl-XL, do Ikaros, e do FGFR4 foi realizado por PCR em tempo real em 20 amostras de corticotropinomas, sendo dois tumores correspondentes à síndrome de Nelson. A determinação dos genótipos no códon 388 do FGFR4 foi realizada nos 97 pacientes e em 103 indivíduos controles, por PCR de fragmento do exon 9 do gene FGFR4 seguida de digestão com a enzima de restrição BstNI. A evolução pós-operatória (remissão/recidiva) da doença de Cushing foi avaliada em 76 pacientes. Foram considerados em remissão aqueles pacientes com níveis normais de cortisol urinário durante todo o primeiro ano após a cirurgia, na ausência de reposição hormonal, bem como os que necessitaram de reposição com glicocorticóide no mesmo período. Resultados: Dos 76 pacientes submetidos à primeira cirurgia transesfenoidal, a remissão pós-operatória ocorreu em 68,4% dos pacientes. Treze pacientes (25%) evoluíram com recidiva da doença de Cushing após remissão inicial. A expressão do Bcl-XL foi semelhante à hipófise normal na maioria das amostras tumorais [mediana (mín-máx): 1,36 (0,6 - 2,70)]. Aumento da expressão das isoformas longas do Ikaros foi detectado em 40% dos tumores, enquanto as isoformas curtas corresponderam a mais de 50% da expressão do Ikaros em apenas 3 casos, não havendo associação da expressão do Ikaros com qualquer das variáveis analisadas. O aumento da expressão do FGFR4 foi detectado em 8/18 (44,4%) dos corticotropinomas com doença de Cushing, havendo associação entre a hiperexpressão do FGFR4 e a menor freqüência de remissão pós-operatória da doença de Cushing (p = 0,009). A distribuição genotípica do polimorfismo G388R foi semelhante entre pacientes e controles. O genótipo glicina em homozigose (Gly/Gly) não foi associado à menor frequência de remissão pós-operatória da doença, no entanto, uma freqüência maior de recidiva pós-operatória foi encontrada no grupo de pacientes Gly/Gly (p = 0,019). O genótipo Gly/Gly foi ainda associado à redução da sobrevida livre de doença (hazard ratio [HR], 6,91; Intervalo de Confiança (IC) de 95%, 1,14 a 11,26; p = 0,028). Outras variáveis que se associaram significativamente com maior freqüência de recidiva foram: tamanho e grau de invasão tumoral de acordo com a classificação de Hardy modificada (p = 0,017), o sexo masculino (p = 0,033), a não confirmação Imuno-histológica do tumor produtor de ACTH (p = 0,026) e os valores de cortisol > 2 ?g/dL no pós-operatório precoce (p = 0,01). Conclusões: A expressão normal detectada do Bcl-XL e das isoformas curtas do Ikaros, na maioria das amostras tumorais, sugere a não participação destes fatores na patogênese dos tumores corticotróficos. O aumento da expressão do FGFR4 e o genótipo glicina em homozigose foram associados, respectivamente, à menor freqüência de remissão e maior recidiva pós-operatória da doença de Cushing. Estes resultados sugerem que o FGFR4 pode ter um papel na progressão dos tumores corticotróficos favorecendo a persistência e/ou recidiva da doença de Cushing. / Introduction: The mechanisms involved in the molecular pathogenesis of corticotroph pituitary tumors are complex, heterogeneous and in most cases remain unknown. Changes in the expression of components of Ikaros (Ik) pathway, such as receptor 4 of fibroblast growth factor (FGFR4), have been detected in pituitary tumors including corticotropinomas. Imbalance between long and short Ik isoforms results in alternative transcription initiation of FGFR4 and encodes a truncated isoform of the gene (pdt-FGFR4) which was associated with larger and more invasive pituitary tumors. The Ik6 short isoform promotes Bcl-XL expression in vitro, an effect independent of the interaction with the long isoforms. In addition, a polymorphism of FGFR4 gene, the substitution of glycine by arginine at codon 388 (G388R), has been associated with adverse outcome in several human tumor types. Objectives: To analyze the expression of Bcl-XL, Ikaros isoforms (Ik1 + Ik2/Ikaros total), and FGFR4 in human corticotropinomas. To determine the frequency of each genotype at codon 388 of FGFR4 in patients with Cushing\'s disease and its association with the postoperative outcome after the first transsphenoidal surgery. Methods: Ninety-seven patients with Cushing\'s disease were evaluated. Clinical, hormonal and histopathological findings were assessed retrospectively. The expression of Bcl-XL, Ikaros and FGFR4 were evaluated by real-time PCR in 20 samples of corticotropinomas, including two samples of Nelson\'s syndrome. The FGFR4 genotype was determined in the 97 patients and 103 control subjects by PCR fragment of exon 9 of the FGFR4 gene, followed by digestion with the BstNI restriction enzyme. The postoperative outcome (remission/relapse) of Cushing\'s disease was assessed in 76 patients. The patients with normal urinary cortisol levels during the first year after surgery, in the absence of hormone replacement therapy, and those who required glucocorticoid replacement within the same period were considered in remission. Results: Of the 76 patients who underwent the first transsphenoidal surgery, remission was achieved in 68.4% of patients. Thirteen patients (25%) developed recurrence of Cushing\'s disease after initial remission. The expression of Bcl-XL in the majority of tumor samples was similar to normal pituitary [median (min-max): 1.36 (0.6 - 2.70)]. Overexpression of long isoforms of Ik was detected in 40% of tumors, while the short isoforms represented more than 50% of the expression in only 3 samples. Ik expression was not associated with any of the variables analysed. FGFR4 transcripts were overexpressed in 8/18 (44.4%) of corticotropinomas with Cushing\'s disease. There was an association between the overexpression of FGFR4 and lower postoperative remission rate (p = 0.009). The FGFR4 genotype distribution at codon 388 was similar between control individuals and patients. The glycine homozygous genotype (Gly/Gly) was not associated with lower remission rate. However, a higher frequency of postoperative recurrence was found in the Gly/Gly group (p = 0.019). The Gly/Gly genotype was also associated with reduced disease-free survival (hazard ratio [HR] 6.91, confidence interval (CI) 95%, 1.14 to 11.26; p = 0.028). Other variables that were significantly associated with higher frequency of recurrence were: size and tumor invasion according to modified Hardy classification (p = 0.017), male gender (p = 0.033), non-immuno-histological confirmation of ACTH secreting tumor (p = 0.026) and cortisol levels > 2 ?g/dL in the early postoperative period (p = 0.01). Conclusions: The normal expression of Bcl-XL and short isoforms of Ik in most samples suggest that these factors are not involved in the pathogenesis of corticotroph tumors. Overexpression of FGFR4 and the glycine homozygous genotype were associated with lower frequency of remission and higher postoperative recurrence of Cushing\'s disease, respectively. These results suggest that FGFR4 may play a role in progression of corticotroph tumors favoring the persistence and/or recurrence of Cushing\'s disease.

Die Recurrence Quantification Analysis (RQA) ist eine Methode aus der nicht-linearen Zeitreihenanalyse. Im Mittelpunkt dieser Methode steht die Auswertung des Inhalts sogenannter Rekurrenzmatrizen. Bestehende Berechnungsansätze zur Durchführung der RQA können entweder nur Zeitreihen bis zu einer bestimmten Länge verarbeiten oder benötigen viel Zeit zur Analyse von sehr langen Zeitreihen. Diese Dissertation stellt die sogenannte skalierbare Rekurrenzanalyse (SRA) vor. Sie ist ein neuartiger Berechnungsansatz, der eine gegebene Rekurrenzmatrix in mehrere Submatrizen unterteilt. Jede Submatrix wird von einem Berechnungsgerät in massiv-paralleler Art und Weise untersucht. Dieser Ansatz wird unter Verwendung der OpenCL-Schnittstelle umgesetzt. Anhand mehrerer Experimente wird demonstriert, dass SRA massive Leistungssteigerungen im Vergleich zu existierenden Berechnungsansätzen insbesondere durch den Einsatz von Grafikkarten ermöglicht. Die Dissertation enthält eine ausführliche Evaluation, die den Einfluss der Anwendung mehrerer Datenbankkonzepte, wie z.B. die Repräsentation der Eingangsdaten, auf die RQA-Verarbeitungskette analysiert. Es wird untersucht, inwiefern unterschiedliche Ausprägungen dieser Konzepte Einfluss auf die Effizienz der Analyse auf verschiedenen Berechnungsgeräten haben. Abschließend wird ein automatischer Optimierungsansatz vorgestellt, der performante RQA-Implementierungen für ein gegebenes Analyseszenario in Kombination mit einer Hardware-Plattform dynamisch bestimmt. Neben anderen Aspekten werden drastische Effizienzgewinne durch den Einsatz des Optimierungsansatzes aufgezeigt. / Recurrence quantification analysis (RQA) is a method from nonlinear time series analysis. It relies on the identification of line structures within so-called recurrence matrices and comprises a set of scalar measures. Existing computing approaches to RQA are either not capable of processing recurrence matrices exceeding a certain size or suffer from long runtimes considering time series that contain hundreds of thousands of data points. This thesis introduces scalable recurrence analysis (SRA), which is an alternative computing approach that subdivides a recurrence matrix into multiple sub matrices. Each sub matrix is processed individually in a massively parallel manner by a single compute device. This is implemented exemplarily using the OpenCL framework. It is shown that this approach delivers considerable performance improvements in comparison to state-of-the-art RQA software by exploiting the computing capabilities of many-core hardware architectures, in particular graphics cards. The usage of OpenCL allows to execute identical SRA implementations on a variety of hardware platforms having different architectural properties. An extensive evaluation analyses the impact of applying concepts from database technology, such memory storage layouts, to the RQA processing pipeline. It is investigated how different realisations of these concepts affect the performance of the computations on different types of compute devices. Finally, an approach based on automatic performance tuning is introduced that automatically selects well-performing RQA implementations for a given analytical scenario on specific computing hardware. Among others, it is demonstrated that the customised auto-tuning approach allows to considerably increase the efficiency of the processing by adapting the implementation selection.

In this doctoral dissertation, we studied and solved several questions regarding positional and abstract numeration systems. Each particular problem is the focus of a chapter. The first problem concerns the study of the preservation of recognizability under multiplication by a constant in abstract numeration systems built on polynomial regular languages. We obtained several results generalizing those from P. Lecomte and M. Rigo. The second problem we considered is a decidability problem, which was already studied, most notably, by J. Honkala and A. Muchnik. For our part, we studied this problem for two new cases: the linear positional numeration systems and the abstract numeration systems. Next, we focused on the extension to the multidimensional setting of a result of A. Maes and M.~Rigo regarding S-automatic infinite words. We obtained a characterization of multidimensional S-automatic words in terms of multidimensional (non-necessarily uniform) morphisms. This result can be viewed as the analogous of O. Salon's extension of a theorem of A. Cobham. Finally, generalizing results of P. Lecomte and M. Rigo, we proposed a formalism to represent real numbers in the general framework of abstract numeration systems built on languages that are not necessarily regular. This formalism encompasses in particular the rational base numeration systems, which have been recently introduced by S. Akiyama, Ch. Frougny, and J. Sakarovitch. Finally, we ended with a list of open questions in the continuation of this work./Dans cette dissertation, nous étudions et résolvons plusieurs questions autour des systèmes de numération abstraits. Chaque problème étudié fait l'objet d'un chapitre. Le premier concerne l'étude de la conservation de la reconnaissabilité par la multiplication par une constante dans des systèmes de numération abstraits construits sur des langages réguliers polynomiaux. Nous avons obtenus plusieurs résultats intéressants généralisant ceux de P. Lecomte et M. Rigo. Le deuxième problème auquel je me suis intéressée est un problème de décidabilité déjà étudié notamment par J. Honkala et A. Muchnik et ici décliné en deux nouvelles versions : les systèmes de numération de position linéaires et les systèmes de numération abstraits. Ensuite, nous nous penchons sur l'extension au cas multidimensionnel d'un résultat d'A. Maes et de M. Rigo à propos des mots infinis S-automatiques. Nous avons obtenu une caractérisation des mots S-automatiques multidimensionnels en termes de morphismes multidimensionnels (non nécessairement uniformes). Ce résultat peut être vu comme un analogue de l'extension obtenue par O. Salon d'un théorème de A. Cobham. Finalement, nous proposons un formalisme de la représentation des nombres réels dans le cadre général des systèmes de numération abstraits basés sur des langages qui ne sont pas nécessairement réguliers. Ce formalisme englobe notamment le cas des numérations en bases rationnelles introduits récemment par S. Akiyama, Ch. Frougny et J. Sakarovitch. Nous terminons par une liste de questions ouvertes dans la continuité de ce travail.

Cette dissertation se divise en deux parties, distinctes mais connexes, qui sont le reflet de la cotutelle. Nous étudions et résolvons des problèmes concernant d'une part la combinatoire des mots dans un contexte abélien et d'autre part des problèmes de couverture dans des graphes. Chaque question fait l'objet d'un chapitre. En combinatoire des mots, le premier problème considéré s'intéresse à la régularité des suites au sens défini par Allouche et Shallit. Nous montrons qu'une suite qui satisfait une certaine propriété de symétrie est 2-régulière. Ensuite, nous appliquons ce théorème pour montrer que les fonctions de complexité 2-abélienne du mot de Thue--Morse ainsi que du mot appelé ''period-doubling'' sont 2-régulières. Les calculs et arguments développés dans ces démonstrations s'inscrivent dans un schéma plus général que nous espérons pouvoir utiliser à nouveau pour prouver d'autres résultats de régularité. Le deuxième problème poursuit le développement de la notion de mot de retour abélien introduite par Puzynina et Zamboni. Nous obtenons une caractérisation des mots sturmiens avec un intercepte non nul en termes du cardinal (fini ou non) de l'ensemble des mots de retour abélien par rapport à tous les préfixes. Nous décrivons cet ensemble pour Fibonacci ainsi que pour Thue--Morse (bien que cela ne soit pas un mot sturmien). Nous étudions la relation existante entre la complexité abélienne et le cardinal de cet ensemble. En théorie des graphes, le premier problème considéré traite des codes identifiants dans les graphes. Ces codes ont été introduits par Karpovsky, Chakrabarty et Levitin pour modéliser un problème de détection de défaillance dans des réseaux multiprocesseurs. Le rapport entre la taille optimale d'un code identifiant et la taille optimale du relâchement fractionnaire d'un code identifiant est comprise entre 1 et 2 ln(|V|)+1 où V est l'ensemble des sommets du graphe. Nous nous concentrons sur les graphes sommet-transitifs, car nous pouvons y calculer précisément la solution fractionnaire. Nous exhibons des familles infinies, appelées quadrangles généralisés, de graphes sommet-transitifs pour lesquelles les solutions entière et fractionnaire sont de l'ordre |V|^k avec k dans {1/4, 1/3, 2/5}. Le second problème concerne les (r,a,b)-codes couvrants de la grille infinie déjà étudiés par Axenovich et Puzynina. Nous introduisons la notion de 2-coloriages constants de graphes pondérés et nous les étudions dans le cas de quatre cycles pondérés particuliers. Nous présentons une méthode permettant de lier ces 2-coloriages aux codes couvrants. Enfin, nous déterminons les valeurs exactes des constantes a et b de tout (r,a,b)-code couvrant de la grille infinie avec |a-b|>4. Il s'agit d'une extension d'un théorème d'Axenovich. / This dissertation is divided into two (distinct but connected) parts that reflect the joint PhD. We study and we solve several questions regarding on the one hand combinatorics on words in an abelian context and on the other hand covering problems in graphs. Each particular problem is the topic of a chapter. In combinatorics on words, the first problem considered focuses on the 2-regularity of sequences in the sense of Allouche and Shallit. We prove that a sequence satisfying a certain symmetry property is 2-regular. Then we apply this theorem to show that the 2-abelian complexity functions of the Thue--Morse word and the period-doubling word are 2-regular. The computation and arguments leading to these results fit into a quite general scheme that we hope can be used again to prove additional regularity results. The second question concerns the notion of return words up to abelian equivalence, introduced by Puzynina and Zamboni. We obtain a characterization of Sturmian words with non-zero intercept in terms of the finiteness of the set of abelian return words to all prefixes. We describe this set of abelian returns for the Fibonacci word but also for the Thue-Morse word (which is not Sturmian). We investigate the relationship existing between the abelian complexity and the finiteness of this set. In graph theory, the first problem considered deals with identifying codes in graphs. These codes were introduced by Karpovsky, Chakrabarty and Levitin to model fault-diagnosis in multiprocessor systems. The ratio between the optimal size of an identifying code and the optimal size of a fractional relaxation of an identifying code is between 1 and 2 ln(|V|)+1 where V is the vertex set of the graph. We focus on vertex-transitive graphs, since we can compute the exact fractional solution for them. We exhibit infinite families, called generalized quadrangles, of vertex-transitive graphs with integer and fractional identifying codes of order |V|^k with k in {1/4,1/3,2/5}. The second problem concerns (r,a,b)-covering codes of the infinite grid already studied by Axenovich and Puzynina. We introduce the notion of constant 2-labellings of weighted graphs and study them in four particular weighted cycles. We present a method to link these labellings with covering codes. Finally, we determine the precise values of the constants a and b of any (r,a,b)-covering code of the infinite grid with |a-b|>4. This is an extension of a theorem of Axenovich.

Cette thèse examine les impacts sur la morphologie des tributaires du fleuve Saint-Laurent des changements dans leur débit et leur niveau de base engendrés par les changements climatiques prévus pour la période 2010–2099. Les tributaires sélectionnés (rivières Batiscan, Richelieu, Saint-Maurice, Saint-François et Yamachiche) ont été choisis en raison de leurs différences de taille, de débit et de contexte morphologique. Non seulement ces tributaires subissent-ils un régime hydrologique modifié en raison des changements climatiques, mais leur niveau de base (niveau d’eau du fleuve Saint-Laurent) sera aussi affecté. Le modèle morphodynamique en une dimension (1D) SEDROUT, à l’origine développé pour des rivières graveleuses en mode d’aggradation, a été adapté pour le contexte spécifique des tributaires des basses-terres du Saint-Laurent afin de simuler des rivières sablonneuses avec un débit quotidien variable et des fluctuations du niveau d’eau à l’aval. Un module pour simuler le partage des sédiments autour d’îles a aussi été ajouté au modèle. Le modèle ainsi amélioré (SEDROUT4-M), qui a été testé à l’aide de simulations à petite échelle et avec les conditions actuelles d’écoulement et de transport de sédiments dans quatre tributaires du fleuve Saint-Laurent, peut maintenant simuler une gamme de problèmes morphodynamiques de rivières. Les changements d’élévation du lit et d’apport en sédiments au fleuve Saint-Laurent pour la période 2010–2099 ont été simulés avec SEDROUT4-M pour les rivières Batiscan, Richelieu et Saint-François pour toutes les combinaisons de sept régimes hydrologiques (conditions actuelles et celles prédites par trois modèles de climat globaux (MCG) et deux scénarios de gaz à effet de serre) et de trois scénarios de changements du niveau de base du fleuve Saint-Laurent (aucun changement, baisse graduelle, baisse abrupte). Les impacts sur l’apport de sédiments et l’élévation du lit diffèrent entre les MCG et semblent reliés au statut des cours d’eau (selon qu’ils soient en état d’aggradation, de dégradation ou d’équilibre), ce qui illustre l’importance d’examiner plusieurs rivières avec différents modèles climatiques afin d’établir des tendances dans les effets des changements climatiques. Malgré le fait que le débit journalier moyen et le débit annuel moyen demeurent près de leur valeur actuelle dans les trois scénarios de MCG, des changements importants dans les taux de transport de sédiments simulés pour chaque tributaire sont observés. Ceci est dû à l’impact important de fortes crues plus fréquentes dans un climat futur de même qu’à l’arrivée plus hâtive de la crue printanière, ce qui résulte en une variabilité accrue dans les taux de transport en charge de fond. Certaines complications avec l’approche de modélisation en 1D pour représenter la géométrie complexe des rivières Saint-Maurice et Saint-François suggèrent qu’une approche bi-dimensionnelle (2D) devrait être sérieusement considérée afin de simuler de façon plus exacte la répartition des débits aux bifurcations autour des îles. La rivière Saint-François est utilisée comme étude de cas pour le modèle 2D H2D2, qui performe bien d’un point de vue hydraulique, mais qui requiert des ajustements pour être en mesure de pleinement simuler les ajustements morphologiques des cours d’eau. / This thesis investigates the impacts of climate-induced changes in discharge and base level on the morphology of Saint-Lawrence River tributaries for the period 2010–2099. The selected tributaries (Batiscan, Richelieu, Saint-Maurice, Saint-François and Yamachiche rivers) were chosen because of their differences in size, flow regime and morphological setting. Not only will these tributaries experience an altered hydrological regime as a consequence of climate change, but their base level (Saint-Lawrence River water level) will also change. A one-dimensional (1D) morphodynamic model (SEDROUT), originally developed for aggrading gravel-bed rivers, was adapted for the specific context of the Saint-Lawrence lowland tributaries in order to simulate sand-bed rivers with variable daily discharge and downstream water level fluctuations. A module to deal with sediment routing in channels with islands was also added to the model. The enhanced model (SEDROUT4-M), which was tested with small-scale simulations and present-day conditions in four tributaries of the Saint-Lawrence River, can now simulate a very wide range of river morphodynamic problems. Changes in bed elevation and bed-material delivery to the Saint-Lawrence River over the 2010–2099 period were simulated with SEDROUT4-M for the Batiscan, Richelieu and Saint-François rivers for all combinations of seven tributary hydrological regimes (present-day and those predicted using three global climate models (GCM) and two greenhouse gas emission scenarios) and three scenarios of how the base level provided by the Saint-Lawrence River will alter (no change, gradual decrease, step decrease). The effects on mean annual sediment delivery and bed elevation differ between GCM and seem to be related to whether the river is currently aggrading, degrading or in equilibrium, which highlights the importance of investigating several rivers using several climate models in order to determine trends in climate change impacts. Despite the fact that mean daily discharge and mean annual maximum discharge remain close to their current values in the three GCM scenarios for daily discharge, marked changes occur in the mean annual sediment transport rates in each simulated tributary. This is due to the important effect of more frequent large individual flood events under future climate as well as a shift of peak annual discharge from the spring towards the winter, which results in increased variability of bed-material transport rates. Some complications with the 1D modelling approach to capture the complex geometry of the Saint-Maurice and Saint-François rivers suggest that the use of a two-dimensional (2D) approach should be seriously considered to accurately simulate the discharge distribution at bifurcations around islands. The Saint-François River is used as a test case for the 2D model H2D2, which performs well from a hydraulics point of view but which needs to be adapted to fully simulate morphological adjustments in the channel.