211 research outputs found
Silibinin, an HSP90 Inhibitor, on Human ACTH-Secreting Adenomas
No full textIntroduction. The glucocorticoid receptor is pivotal to control corticotrophin (ACTH) secretion and its function is closely linked to the heat shock protein 90 (HSP90) chaperone complex. Impaired sensitivity to glucocorticoid feedback is a hallmark of human corticotroph adenomas, i.e., Cushing's disease, a disorder with few medical treatment options. Silibinin, a HSP90 inhibitor, has been studied in tumoral corticotroph cells and its use proposed in Cushing's disease. Aim of the present study was to further investigate the effect of silibinin on human corticotroph adenomas in vitro.Methods. Seven human ACTH-secreting pituitary adenomas were established in culture and treated with 10 - 50 mu M silibinin with/without dexamethasone for up to 72 hours. ACTH medium levels were measured and POMC and glucocorticoid receptor, i.e., NR3C1, gene expression assessed.Results. Silibinin reduced spontaneous ACTH secretion and restored sensitivity to steroid negative feedback to a different extent in individual adenomas. POMC expression was decreased both in control and dexamethasone-treated wells in specimens sensitive to silibinin. Interestingly, silibinin reduced constitutive NR3C1 expression and reversed the dexamethasone-induced inhibition.Conclusions. Our findings indicate that silibinin can inhibit ACTH synthesis and secretion in individual human corticotroph adenomas and directly affects NR3C1 gene expression. These results reveal promising effects of this HSP90 inhibitor on human corticotroph adenomas and support an innovative target treatment for patients with Cushing's disease
Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas
No full textPurpose: somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been described in patients with Cushing’s disease (CD). The aim of the study is to verify whether USP8 mutation may predict early and late outcome of pituitary surgery in patients with CD operated at a single institution. Methods: We performed a retrospective genetic analysis of 92 adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Specimens were screened for USP8 hotspot mutations in the exon 14 with Sanger sequencing. Hormonal and surgical data were compared between USP8 variant carriers and wild-type tumors. Results: USP8 variants were detected in 22 adenomas (23.9%) with higher prevalence in women (28.9% vs. 5.3% in men; p < 0.05). No significant difference in hormonal levels and tumoral features in relation to USP8 status was observed. Interestingly, USP8-variant carriers were more likely to achieve surgical remission than wild-type adenomas (100% vs. 75.7%; p = 0.01). Conversely, recurrence of CD occurred in 23% of USP8-mutated patients and in 13% of patients with wild-type adenoma. The recurrence-free survival did not differ significantly between the two groups (p = 0.42). Conclusions: ACTH-secreting pituitary adenomas carrying somatic USP8 mutations are associated with a greater likelihood of surgical remission in patients operated by a single neurosurgeon. Recurrence rates are not related with USP8-variant status
Environmentally friendly road barriers
No full textRoad safety barriers are a passive safety system and usually they are made of steel or cement concrete. Ac-tually, road barriers made of wood and steel are located in context of particular environmental value (moun-tains, countryside, or along a road close to a park or in a park).
The aim of this research is a new safety road barrier made completely of wood.
Wood is a material with a complex structure, whose main features are anisotropy and hygroscopicity. It al-so possesses greatly different mechanics characteristics between the longitudinal direction and the tangential and radial direction.
In Europe, road safety barriers have to pass crash tests required by EN1317 before their location. So in this study, several barriers have been designed and modelled and, for each of them, impact with a vehicle has been simulated with the software Ls-Dyna, following EN 1317 prescriptions. Analysis of the different models and their compliance with the requirements of the Standard, has allowed the authors to identify the optimal sec-tion of beams and posts, the distance between beams and between posts of the new barrier.
Furthermore, a parametric analysis has been conducted, to examine how temperature and humidity can modify mechanical characteristics of wood and so performance of the new barrier.
The results appeared interesting: the new barrier satisfied all requirements prescribed by the Regulation and the parametric study highlighted that THIV (Theoretical Head Impact Velocity) and ASI (Acceleration Severity Index) vary with temperature and humidity but their values were always below the limit imposed by EN 1317.
This study represents only one step of the research which needs more data to individuate a correlation be-tween temperature and humidity and ASI and THIV indexes, and a real scale test to calibrate the model
Selbstübersetzung bei Ilse Losa
No full textDie Diplomarbeit behandelt das Thema Selbstübersetzung bei der deutsch-portugiesischen Autorin Ilse Losa, insbesondere den Roman Sob Céus Estranhos (1962) und die darauf basierende Übersetzung Unter fremden Himmeln (1991). Losa, die den Großteil ihrer Werke auf Portugiesisch verfasste, griff erst spät auf Deutsch als Literatursprache zurück. Im Zentrum der Arbeit steht eine komparative Analyse zwischen den beiden Romanen und die Frage, wie und in welcher Form zwei Texte sich nach dreißig Jahren und einem Schreibprozesses mit/ohne Zensur verändern können. Dabei zuerst erfolgt eine Beschäftigung mit Ilse Losas Leben deren Erlebnisse im Exil ihr Werk beeinflussten. Anschließend beschäftigt sich die Arbeit mit den Ereignissen die zum Estado Novo führten, Methoden und Ideologien werden näher beleuchtet. Ein weiteres Kapitel, das Losas Leben, die Diktatur und den Roman verbindet, behandelt die wenig bekannte Rolle Portugals im Zweiten Weltkrieg und als Transit- und Flüchtlingsland. Darauf folgt ein Kapitel zur Sprachfindung oder Sprachwahl Losas. Diese Entscheidung und der Konflikt, der bei Losa daraus resultiert, sind eng mit den später angefertigten Selbstübersetzungen verbunden. Deshalb wird ein Überblick über theoretische Ansätze zur Selbstübersetzung gegeben und versucht, diese Erklärungsversuche auf Ilse Losa umzulegen, beziehungsweise auch aufzuzeigen, was dazu führte, dass sie sich selbst übersetzte. Der Hauptteil der Arbeit beschäftigt sich mit dem Vergleich der zwei Romane. Dazu werden zuerst Informationen über thematische und formale Aspekte des Textes gegeben. Die Texte wurden einander gegenübergestellt und vor allem in Hinblick auf politische und kulturelle Unterschiede, auf die eine politische wie moralische Zensur am meisten Einfluss haben konnte, untersucht.This thesis deals with self-translation in the case of the German-Portuguese author Ilse Losa, in particular the novel Sob Céus Estranhos (1962) and its German translation Unter fremden Himmeln (1991). Losa wrote most of her oeuvre in Portuguese and only in her later years switched to her native language German. The main object of this dissertation is a comparative analysis based on the question how thirty years between the writing of the original and its translation can affect the text, especially when the novel is created during a period of censorship. Her works were mainly influenced of her experiences in exile, so here biography will summarised. As the censorship and the political regime influenced her work too, one chapter will outline the events that led to the foundation of the Estado Novo and its governmental methods and ideologies. Also the lesser-known role of Portugal during the Second World War as well as the part it played as a transit and refugee country will be explained
Losas choice to write Portuguese resulted in a personal conflict at the end of her life and can be seen as connection to her decision to self-translation. Thus, reasons for her choice of language and various theoretical approaches to self-translation will be given and applied on Losa. The main part of the thesis concentrates on the comparative analysis of the two novels. Some information about the novel’s thematic and formal aspects will be summarised and finally the texts are compared with each other
Proopiomelanocortin, glucocorticoid, and CRH receptor expression in human ACTH-secreting pituitary adenomas
No full textACTH-secreting pituitary tumors are by definition partially autonomous, i.e., secrete ACTH independent of physiological control. However, only few, small-sized studies on proopiomelanocortin (POMC) and its regulation by corticotropin-releasing hormone (CRH) or glucocorticoids are available. Objective of the present study was to report on constitutive and CRH- and dexamethasone-regulated POMC, CRH (CRH-R1), and glucocorticoid receptor (NR3C1) gene expression in a large series of human corticotrope adenomas. Fifty-three ACTH-secreting adenomas were incubated with 10 nM CRH or 10 nM dexamethasone for 24 h. POMC, CRH-R1,NR3C1, and its alpha and beta isoforms were quantified and medium ACTH measured. Constitutive POMC expression proved extremely variable, with macroadenomas exhibiting higher levels than microadenomas. POMC increased during CRH in most specimens; conversely, changes induced by dexamethasone were varied, ranging from decrease to paradoxical increase. No correlation between POMC and ACTH was detected in any experimental condition. CRH-R1 expression was not linked to the response to CRH while NR3C1 was expressed at greater levels in specimens who failed to inhibit during dexamethasone; glucocorticoid receptor α was the more abundant isoform and subject to down-regulation by dexamethasone. Our results demonstrate a considerable variability in POMC expression among tumors and no correlation between POMC and ACTH, suggesting that POMC peptide processing/transport plays a major role in modulating ACTH secretion. Further, CRH-R1 and NR3C1 expression were not linked to the expected ligand-induced outcome, indicating that receptor signaling rather than abundance determines corticotrope responses. Our findings pave the way to new avenues of research into Cushing’s disease pathophysiology
Quantification of Black Carbon Emissions from Gas Flaring and Standardization of the Sky-LOSA Measurement Technique
No full textThis thesis details the deployment and refinement of an emergent optical diagnostic for soot/black carbon (BC) emissions from gas flaring alongside investigations into optical properties of flare BC. Research efforts were first focussed on the field-deployment of the existing sky-LOSA (line-of-sight attenuation using skylight) technique to measure BC emissions from gas flares. Fourteen measurements from nine flares revealed BC emissions spanning more than four orders of magnitude, highlighting the disproportionate emissions contributions of individual "super-emitting" flares. BC yields measured at four flares varied with flare gas energy content, permitting extension of a laboratory-based emission factor model to consider field data for actual in-field flares. Available gas flare simulation data were subsequently leveraged to perform numerical simulations of radiative transfer through realistic flare plumes to quantify previously ignored radiative effects in the sky-LOSA algorithm. Refractive index gradient-driven beam steering was found to be negligible through cooled flare plumes. By contrast, multiple scattering was observed to significantly affect inscattering within the radiative transfer theory for sky-LOSA. These data revealed a simple model to correct for multiple scattering effects in the sky-LOSA algorithm with negligible impact on measurement uncertainties as evidenced by case study analyses. Laboratory studies of flare BC were performed in parallel to address a lack of data for flare-relevant BC mass-normalized absorption cross-section (MAC). BC MAC was quantified for myriad flare gas compositions/conditions and varied with numerous flare metrics. A phenomenological model for BC MAC was developed using a novel scaling parameter thought to capture the in-flame time-temperature history of BC particulate. The new model reconciled anomalous field data and suggested that flare BC MAC might be >1.3−2.0 times larger than other sources. The final focus of this thesis was the completion of a general uncertainty analysis (GUA) to support standardized setup and measurement protocols for sky-LOSA. Uncertainties over all practical measurement conditions were computed in a variance-reduced Monte Carlo framework. GUA data were compiled and presented in a new open-source software tool to allow sky-LOSA users to consistently obtain optimal measurement data for arbitrary measurement conditions, enabling broader deployment of sky-LOSA to quantify and reduce flare BC emissions
Cushing's disease due to double pituitary ACTH-secreting adenomas: the first case report
No full textDouble pituitary adenomas are rare occurences in autoptical, surgical and neuroradiological series and are mostly due to non-functioning pituitary adenomas, GH-secreting and prolactin-secreting adenomas. ACTH secreting tumours are more rare and, to our knowledge, two distinct ACTH-producing adenomas within the same pituitary have never been reported. We herewith describe a 56 year old woman with Cushing's disease due to two clearly distinct ACTH-secreting pituitary adenomas. She presented with signs and symptoms of hypercortisolism and hormonal testing was indicative for pituitary-dependent Cushing's syndrome. Sellar MRI visualized an asymmetric pituitary gland with suspect lesions in both the right and the left pituitary lobes. Both lesions were removed during transsphenoidal surgery and remission of hypercortisolism ensued. Pathology confirmed the existence of two distinct adenomas located in different sites in the gland. Both presented ACTH immunoreactivity but displayed distinct morphological features. Our case indicates that double ACTH-secreting pituitary adenomas may occur in patients with Cushing's disease. Careful radiological, surgical and pathological examination is necessary to recognize this condition and avoid surgical failure. © The Japan Endocrine Society
Writing from the margins: the Crónicas of Ilse Losa
No full textEsta tese examina as crónicas coligidas e não-coligidas da autora portuguesa de origens judia alemãs, Ilse Losa (1913-2006). Abrangendo um período de cinco décadas, de 1948 até aos
primeiros anos da década de 1990, as crónicas refletem não só a trajetória pessoal de integração
de Losa, mas também o contexto sociopolítico português enquanto este sofreu as
transformações profundas da segunda metade do século vinte. Tal como Losa, que, como
autora (mulher) de origens estrangeiras, representa para a sociedade e cultura portuguesas uma
identidade marginal a vários níveis, a crónica, como género que se localiza entre diferentes e
aparentemente contrastantes campos discursivos (como os da literatura, da história e do
jornalismo) tende a ser subvalorizada nos estudos literários portugueses. Como resultado, este
aspecto específico da obra da autora representa uma área da literatura portuguesa que, até ao
momento, tem sido duplamente negligenciado pela academia. A tese dedica minuciosa atenção
aos três volumes de crónicas losianas – Ida e Volta: À Procura de Babbitt (1960), Estas Searas
(1984) e À Flor do Tempo (1997); também explora arquivos que contêm textos que Losa
publicava regularmente em revistas e jornais mas que ainda não se encontram em coleções
editadas. O resultante retrato de “Ilse Losa, cronista” que se revela é o de alguém que estava
profunda, consistente e atrevidamente comprometida com questões de justiça social,
frequentemente contornando com destreza a censura do Estado Novo para conseguir expressar
as suas opiniões progressistas e portanto polémicas. Ao combinar dados quantitativos e
qualitativos do arquivo da família Losa com os de quatro estudos de caso (Vértice, Seara Nova,
Diário de Lisboa e Público), a tese, além de desenvolver uma impressão mais nítida da crónica
losiana ao longo das cinco décadas da sua produção, incorpora uma discussão e ilustração
prática da importância de uma abordagem transparente ao trabalho de arquivo.This thesis examines the collated and uncollated crónicas of Jewish-German-born author of
Portuguese literature, Ilse Losa (1913-2006). Spanning a period of five decades, from 1948 to
the early 1990s, the crónicas reflect not only Losa’s personal trajectory of increasing
integration in Portuguese society, but also the Portuguese socio-political context as this
underwent radical transformation throughout the latter half of the twentieth century. Just as
Losa herself, who, as a foreign-born, female writer, represents a multiply marginal figure in
Portuguese society and culture, the crónica, as a genre which sits between different, apparently
distinct discursive fields (such as those of literature and history, or literature and journalism)
has tended to be undervalued within Portuguese literary studies. As such, this particular aspect
of this particular author’s oeuvre represents an area of Portuguese literature which, so far, has
been doubly neglected by scholars. The thesis gives thorough attention to the three published
volumes containing Losian crónicas – Ida e Volta: À Procura de Babbitt (1960), Estas Searas
(1984) and À Flor do Tempo (1997) – as well as embarking on an exploration of archives
containing texts which Losa regularly published in periodicals and newspapers but which have
not been reproduced in anthologised collections. The impression of Losa’s cronista identity
which emerges is of someone thoroughly, consistently and boldly engaged with issues of social
justice, frequently and skilfully navigating Estado Novo censorship in order to express her
controversially progressive views. Combining quantitative and qualitative data from the Losa
family archive plus four case studies (Vértice, Seara Nova, Diário de Lisboa and Público),
beyond developing a fuller picture of the Losian crónica across the five decades of its
production, the thesis also incorporates a discussion and practical illustration of the need for a
transparent approach to archival work
Writing from the margins: the Crónicas of Ilse Losa
No full textEsta tese examina as crónicas coligidas e não-coligidas da autora portuguesa de origens judia alemãs, Ilse Losa (1913-2006). Abrangendo um período de cinco décadas, de 1948 até aos
primeiros anos da década de 1990, as crónicas refletem não só a trajetória pessoal de integração
de Losa, mas também o contexto sociopolítico português enquanto este sofreu as
transformações profundas da segunda metade do século vinte. Tal como Losa, que, como
autora (mulher) de origens estrangeiras, representa para a sociedade e cultura portuguesas uma
identidade marginal a vários níveis, a crónica, como género que se localiza entre diferentes e
aparentemente contrastantes campos discursivos (como os da literatura, da história e do
jornalismo) tende a ser subvalorizada nos estudos literários portugueses. Como resultado, este
aspecto específico da obra da autora representa uma área da literatura portuguesa que, até ao
momento, tem sido duplamente negligenciado pela academia. A tese dedica minuciosa atenção
aos três volumes de crónicas losianas – Ida e Volta: À Procura de Babbitt (1960), Estas Searas
(1984) e À Flor do Tempo (1997); também explora arquivos que contêm textos que Losa
publicava regularmente em revistas e jornais mas que ainda não se encontram em coleções
editadas. O resultante retrato de “Ilse Losa, cronista” que se revela é o de alguém que estava
profunda, consistente e atrevidamente comprometida com questões de justiça social,
frequentemente contornando com destreza a censura do Estado Novo para conseguir expressar
as suas opiniões progressistas e portanto polémicas. Ao combinar dados quantitativos e
qualitativos do arquivo da família Losa com os de quatro estudos de caso (Vértice, Seara Nova,
Diário de Lisboa e Público), a tese, além de desenvolver uma impressão mais nítida da crónica
losiana ao longo das cinco décadas da sua produção, incorpora uma discussão e ilustração
prática da importância de uma abordagem transparente ao trabalho de arquivo.This thesis examines the collated and uncollated crónicas of Jewish-German-born author of
Portuguese literature, Ilse Losa (1913-2006). Spanning a period of five decades, from 1948 to
the early 1990s, the crónicas reflect not only Losa’s personal trajectory of increasing
integration in Portuguese society, but also the Portuguese socio-political context as this
underwent radical transformation throughout the latter half of the twentieth century. Just as
Losa herself, who, as a foreign-born, female writer, represents a multiply marginal figure in
Portuguese society and culture, the crónica, as a genre which sits between different, apparently
distinct discursive fields (such as those of literature and history, or literature and journalism)
has tended to be undervalued within Portuguese literary studies. As such, this particular aspect
of this particular author’s oeuvre represents an area of Portuguese literature which, so far, has
been doubly neglected by scholars. The thesis gives thorough attention to the three published
volumes containing Losian crónicas – Ida e Volta: À Procura de Babbitt (1960), Estas Searas
(1984) and À Flor do Tempo (1997) – as well as embarking on an exploration of archives
containing texts which Losa regularly published in periodicals and newspapers but which have
not been reproduced in anthologised collections. The impression of Losa’s cronista identity
which emerges is of someone thoroughly, consistently and boldly engaged with issues of social
justice, frequently and skilfully navigating Estado Novo censorship in order to express her
controversially progressive views. Combining quantitative and qualitative data from the Losa
family archive plus four case studies (Vértice, Seara Nova, Diário de Lisboa and Público),
beyond developing a fuller picture of the Losian crónica across the five decades of its
production, the thesis also incorporates a discussion and practical illustration of the need for a
transparent approach to archival work
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