Non-acute Transient Reversible Adrenal Insufficiency in a Survivor of Critical Illness: A Lesser-known Cause of Primary Adrenal Insufficiency

Objectives: Primary adrenal insufficiency AI is regarded as a progressive disease needing lifelong replacement therapy, but this may not always be the case. Material and methods: A non-acute presentation of AI following a hypotensive episode caused by blood loss was investigated. Results: Adrenal function fully recovered without treatment. Conclusions: There should be a high index of suspicion and a low threshold for performing tests of adrenal function in survivors of critical illness and severe hypotensive episodes.

Iatrogenic Cushing’s syndrome and Secondary Adrenal Insufficiency in an HIV Patientreceiving Fluticasone and Ritonavir

Objectives: To illustrate that the protease inhibitor (PI) ritonavir, widely used as part of the treatment for HIV, might cause drug–drug interactions with inhaled corticosteroids. Material and methods: A case report is presented. Results: An HIV-positive patient presented with gradually changing body composition that was ascribed to lipodystrophy. Finally, iatrogenic Cushing's syndrome with secondary adrenal insufficiency was diagnosed due to a drug–drug interaction of ritonavir and fluticasone. Conclusion: Lipodystrophy might mimic Cushing's syndrome. The combination of ritonavir and inhaled fluticasone may lead to systemic steroid excess causing Cushing's syndrome and secondary adrenal insufficiency.

Probabilistic design optimization of horizontal axis wind turbine rotors

Considerable interest in renewable energy has increased in recent years due to the concerns raised over the environmental impact of conventional energy sources and their price volatility. In particular, wind power has enjoyed a dramatic global growth in installed capacity over the past few decades. Nowadays, the advancement of wind turbine industry represents a challenge for several engineering areas, including materials science, computer science, aerodynamics, analytical design and analysis methods, testing and monitoring, and power electronics. In particular, the technological improvement of wind turbines is currently tied to the use of advanced design methodologies, allowing the designers to develop new and more efficient design concepts. Integrating mathematical optimization techniques into the multidisciplinary design of wind turbines constitutes a promising way to enhance the profitability of these devices. In the literature, wind turbine design optimization is typically performed deterministically. Deterministic optimizations do not consider any degree of randomness affecting the inputs of the system under consideration, and result, therefore, in an unique set of outputs. However, given the stochastic nature of the wind and the uncertainties associated, for instance, with wind turbine operating conditions or geometric tolerances, deterministically optimized designs may be inefficient. Therefore, one of the ways to further improve the design of modern wind turbines is to take into account the aforementioned sources of uncertainty in the optimization process, achieving robust configurations with minimal performance sensitivity to factors causing variability. The research work presented in this thesis deals with the development of a novel integrated multidisciplinary design framework for the robust aeroservoelastic design optimization of multi-megawatt horizontal axis wind turbine (HAWT) rotors, accounting for the stochastic variability related to the input variables. The design system is based on a multidisciplinary analysis module integrating several simulations tools needed to characterize the aeroservoelastic behavior of wind turbines, and determine their economical performance by means of the levelized cost of energy (LCOE). The reported design framework is portable and modular in that any of its analysis modules can be replaced with counterparts of user-selected fidelity. The presented technology is applied to the design of a 5-MW HAWT rotor to be used at sites of wind power density class from 3 to 7, where the mean wind speed at 50 m above the ground ranges from 6.4 to 11.9 m/s. Assuming the mean wind speed to vary stochastically in such range, the rotor design is optimized by minimizing the mean and standard deviation of the LCOE. Airfoil shapes, spanwise distributions of blade chord and twist, internal structural layup and rotor speed are optimized concurrently, subject to an extensive set of structural and aeroelastic constraints. The effectiveness of the multidisciplinary and robust design framework is demonstrated by showing that the probabilistically designed turbine achieves more favorable probabilistic performance than those of the initial baseline turbine and a turbine designed deterministically.

Acute Transient Stress Induced Adrenal Hypertrophy and Adrenal Medullary Hyperactivity

Objectives: Adrenal gland hypertrophy can be related to acute stress with abnormal adrenal function tests. It may not always need treatment. Material and methods: An acute presentation of adrenal gland hypertrophy following an abdominal emergency, with subsequent hypoadrenalism was investigated. Results: Adrenal medullary and cortical function fully recovered without treatment. Conclusions: We postulate that the adrenal glands became enlarged and hypertrophied during an acute stress event, possibly caused by acute adrenal medullary hypersecretion and subsequent cortical hyposecretion. A wait and watch policy should be followed if no other clinical symptoms and signs of adrenal disease are present. CT scan remains an important diagnostic tool.

An improved method for the detection of heterozygosity of congenital virilizing adrenal hyperplasia

SCOPUS: ar.j

Ontogeny and nutritional programming of the hepatic growth hormone-insulin-like growth factor-prolactin axis in the sheep

The liver is an important metabolic and endocrine organ in the fetus but the extent to which its hormone receptor (R) sensitivity is developmentally regulated in early life is not fully established. We, therefore, examined developmental changes in mRNA abundance for the growth hormone (GH) and prolactin (PRL) receptors (R) plus insulin-like growth factor (IGF)-I and –II and their receptors. Fetal and postnatal sheep were sampled at either 80, or 140 days gestation, 1, 30 days or six months of age. The effect of maternal nutrient restriction between early to mid (i.e. 28 to 80 days gestation, the time of early liver growth) gestation on gene expression was also examined in the fetus and juvenile offspring. Gene expression for the GHR, PRLR and IGF-IR increased through gestation peaking at birth, whereas IGF-I was maximal near to term. In contrast, IGF-II mRNA decreased between mid and late gestation to increase after birth whereas IGF-IIR remained unchanged. A substantial decline in mRNA abundance for GHR, PRLR and IGF-IR then occurred up to six months. Maternal nutrient restriction reduced GHR and IGF-IIR mRNA abundance in the fetus, but caused a precocious increase in the PRLR. Gene expression for IGF-I and –II were increased in juvenile offspring born to nutrient restricted mothers. In conclusion, there are marked differences in the developmental ontogeny and nutritional programming of specific hormones and their receptors involved in hepatic growth and development in the fetus. These could contribute to changes in liver function during adult life.

Effects of aqueous extract from Asparagus officinalis L. roots on hypothalamic-pituitary-gonadal axis hormone levels and the number of ovarian follicles in adult rats

Background: Asparagus is a plant with high nutritional, pharmaceutical, and industrial values. Objective: The present study aimed to evaluate the effect of aqueous extract of asparagus roots on the hypothalamic-pituitary-gonadal axis hormones and oogenesis in female rats. Materials and Methods: In this experimental study, 40 adult female Wistar rats were divided into five groups, which consist 8 rats. Groups included control, sham and three experimental groups receiving different doses (100, 200, 400 mg/kg/bw) of aqueous extract of asparagus roots. All dosages were administered orally for 28 days. Blood samples were taken from rats to evaluate serum levels of Gonadotropin releasing hormone (GnRH), follicular stimulating hormone (FSH), Luteinal hormone (LH), estrogen, and progesterone hormones. The ovaries were removed, weighted, sectioned, and studied by light microscope. Results: Dose-dependent aqueous extract of asparagus roots significantly increased serum levels of GnRH, FSH, LH, estrogen, and progestin hormones compared to control and sham groups. Increase in number of ovarian follicles and corpus luteum in groups treated with asparagus root extract was also observed (p<0.05). Conclusion: Asparagus roots extract stimulates secretion of hypothalamic- pituitary- gonadal axis hormones. This also positively affects oogenesis in female rats.

Caracterização clínica, metabólica e hormonal de portadores de lipodistrofia parcial familiar

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2015.

The Economic and Aesthetic Axis of Information Organization Frameworks

This paper argues that in order to systematically comprehend the diversity of information organization frameworks, we must look at how aesthetic concerns and economic concerns manifest in decisions made about designing and deploying work practices, structures, and discourse. In order to do this I construct an analytical rubric borne by a definition of aesthetic and economics pertinent to indexing regimes. I take the position that we need to move into a more descriptive stance on practices of knowledge organization, not only in documentary heritage institutions (libraries, archives, and museums), but also into the cultural and artistic realms. By expanding the scope of inquiry we can interrogate the integrity of my assertion above, namely, that a chief concern in systematically understanding information organization frameworks, lies in understanding how such frameworks wrestle with, and manifest along a spectrum drawn from economic to aesthetic decision-making.

Modeling the Aesthetic Axis of Information Organization Frameworks, Part 1: Theoretical Basis

Purpose – The purpose of this paper is to propose a theoretical framework, based on contemporary philosophical aesthetics, from which principled assessments of the aesthetic value of information organization frameworks may be conducted.Design/methodology/approach – This paper identifies appropriate discourses within the field of philosophical aesthetics, constructs from them a framework for assessing aesthetic properties of information organization frameworks. This framework is then applied in two case studies examining the Library of Congress Subject Headings (LCSH), and Sexual Nomenclature: A Thesaurus. Findings – In both information organization frameworks studied, the aesthetic analysis was useful in identifying judgments of the frameworks as aesthetic judgments, in promoting discovery of further areas of aesthetic judgments, and in prompting reflection on the nature of these aesthetic judgments. Research limitations/implications – This study provides proof-of-concept for the aesthetic evaluation of information organization frameworks. Areas of future research are identified as the role of cultural relativism in such aesthetic evaluation and identification of appropriate aesthetic properties of information organization frameworks.Practical implications – By identifying a subset of judgments of information organization frameworks as aesthetic judgments, aesthetic evaluation of such frameworks can be made explicit and principled. Aesthetic judgments can be separated from questions of economic feasibility, functional requirements, and user-orientation. Design and maintenance of information organization frameworks can be based on these principles.Originality/value – This study introduces a new evaluative axis for information organization frameworks based on philosophical aesthetics. By improving the evaluation of such novel frameworks, design and maintenance can be guided by these principles.Keywords Evaluation, Research methods, Analysis, Bibliographic systems, Indexes, Retrieval languages

Modeling the Aesthetic Axis of Information Organization Frameworks, Part 2: Case Studies

Purpose – The purpose of this paper is to propose a theoretical framework, based on contemporary philosophical aesthetics, from which principled assessments of the aesthetic value of information organization frameworks may be conducted.Design/methodology/approach – This paper identifies appropriate discourses within the field of philosophical aesthetics, constructs from them a framework for assessing aesthetic properties of information organization frameworks. This framework is then applied in two case studies examining the Library of Congress Subject Headings (LCSH), and Sexual Nomenclature: A Thesaurus. Findings – In both information organization frameworks studied, the aesthetic analysis was useful in identifying judgments of the frameworks as aesthetic judgments, in promoting discovery of further areas of aesthetic judgments, and in prompting reflection on the nature of these aesthetic judgments. Research limitations/implications – This study provides proof-of-concept for the aesthetic evaluation of information organization frameworks. Areas of future research are identified as the role of cultural relativism in such aesthetic evaluation and identification of appropriate aesthetic properties of information organization frameworks.Practical implications – By identifying a subset of judgments of information organization frameworks as aesthetic judgments, aesthetic evaluation of such frameworks can be made explicit and principled. Aesthetic judgments can be separated from questions of economic feasibility, functional requirements, and user-orientation. Design and maintenance of information organization frameworks can be based on these principles.Originality/value – This study introduces a new evaluative axis for information organization frameworks based on philosophical aesthetics. By improving the evaluation of such novel frameworks, design and maintenance can be guided by these principles.Keywords Evaluation, Analysis, Bibliographic systems, Indexes, Retrieval languages, Philosophy

Caractérisation du potentiel de champ locale dans le cortex préfrontal médian du rat durant le stress et la prise alimentaire

Le stress joue un rôle important dans le maintien de la qualité de vie quotidienne. Une exposition à une situation stressante peut causer divers désordres neuropsychiatriques du cerveau qui sont associés avec des problèmes liés au sommeil, à la dépression, à des problèmes digestifs et à des troubles de l’alimentation. Les traitements de ces troubles liés au stress sont très coûteux à travers le monde. De nos jours, des considérations importantes ont été soulevées afin de trouver des moyens appropriés pour la prévention plutôt que de dépenser ultérieurement plus de budget sur les traitements. De cette façon, l’étude et l’expérimentation sur les animaux des troubles liés au stress sont l’un des moyens les plus fiables pour atteindre une compréhension plus profonde des problèmes liés au stress. Ce projet visait à révéler la modulation des potentiels de champ locaux (LFP) lors de la consommation de sucrose dans deux conditions englobant la condition de contrôle non-stressante et celle stressante d’un choc électrique aiguë à la patte dans le cortex préfrontal médian (CPFm) du cerveau de rat. Le CPFm est une structure importante dans la réponse au stress et à l’anxiété par l’interaction avec l’axe hypothalamique-pituitaire surrénale (HPA). Les résultats de ce projet ont révélé que la plupart des coups de langue se sont produits dans les 15 premières minutes de l’accès à une solution de sucrose autant pour la condition contrôle non-stressante que pour la condition stressante. En outre, le stress aigu d’un choc à la patte affecte de manière significative la consommation horaire de sucrose en diminuant le volume de la consommation. Les résultats ont également révélé une présence importante du rythme thêta dans le CPFm pendant la condition de base et pendant l’ingestion de sucrose dans les deux conditions. De plus, les résultats ont montré une diminution de puissance des bandes delta et thêta lors des initiations de léchage du sucrose. Ce projet conduit à des informations détaillées sur les propriétés électrophysiologiques du cortex infra-limbique (IL) du CPFm en réponse à l’exposition à des conditions de stress et de l’apport d’une solution de sucrose. Ce projet permet également de mieux comprendre les mécanismes neurophysiologiques des neurones du CPFm en réponse à l’exposition à une condition stressante suivie d’apport de sucrose. Ce projet a également permis de confirmer les effets anorexigènes du stress et suggèrent également que la synchronisation neuronale dans le cortex IL peut jouer un rôle dans le comportement de léchage et sa désynchronisation pendant le léchage après une exposition à des conditions stressantes.

MicroRNA modulation of aldosterone production in the adrenal gland

Hypertension is the major risk factor for coronary disease worldwide. Primary hypertension is idiopathic in origin but is thought to arise from multiple risk factors including genetic, lifestyle and environmental influences. Secondary hypertension has a more definite aetiology; its major single cause is primary aldosteronism (PA), the greatest proportion of which is caused by aldosteroneproducing adenoma (APA), where aldosterone is synthesized at high levels by an adenoma of the adrenal gland. There is strong evidence to show that high aldosterone levels cause adverse effects on cardiovascular, cerebrovascular, renal and other systems. Extensive studies have been conducted to analyse the role that regulation of CYP11B2, the gene encoding the aldosterone synthase enzyme plays in determining aldosterone production and the development of hypertension. One significant regulatory factor that has only recently emerged is microRNA (miRNA). miRNAs are small non-coding RNAs, synthesized by a series of enzymatic processes, that negatively regulate gene expression at the posttranscriptional level. Detection and manipulation of miRNA is now known to be a viable method in the treatment, prevention and prognosis of certain diseases. The aim of the present study was to identify miRNAs likely to have a role in the regulation of corticosteroid biosynthesis. To achieve this, the miRNA profile of APA and normal human adrenal tissue was compared, as was the H295R adrenocortical cell line model of adrenocortical function, under both basal conditions and following stimulation of aldosterone production. Key differentially-expressed miRNAs were then identified and bioinformatic tools used to identify likely mRNA targets and pathways for these miRNAs, several of which were investigated and validated using in vitro methods. The background to this study is set out in Chapter 1 of this thesis, followed by a description of the major technical methods employed in Chapter 2. Chapter 3 presents the first of the study results, analysing differences in miRNA profile between APA and normal human adrenal tissue. Microarray was implemented to detect the expression of miRNAs in these two tissue types and several miRNAs were found to vary significantly and consistently between them. Furthermore, members of several miRNA clusters exhibited similar changes in expression pattern between the two tissues e.g. members of cluster miR-29b-1 (miR-29a-3p and miR-29b-3p) and of cluster miR-29b-2 (miR-29b-3p and miR-29c- 3p) are downregulated in APA, while members of cluster let-7a-1 (let-7a-5p and let-7d-5p), cluster let-7a-3 (let-7a-5p and let-7b-5p) and cluster miR-134 (miR- 134 and miR-382) are upregulated. Further bioinformatic analysis explored the possible biological function of these miRNAs using Ingenuity® Systems Pathway Analysis software. This led to the identification of validated mRNAs already known to be targeted by these miRNAs, as well as the prediction of other mRNAs that are likely targets and which are involved in processes relevant to APA pathology including cholesterol synthesis (HMGCR) and corticosteroidogenesis (CYP11B2). It was therefore hypothesised that increases in miR-125a-5p or miR- 335-5p would reduce HMGCR and CYP11B2 expression. Chapter 4 describes the characterisation of H295R cells of different strains and sources (H295R Strain 1, 2, 3 and HAC 15). Expression of CYP11B2 was assessed following application of 3 different stimulants: Angio II, dbcAMP and KCl. The most responsive strain to stimulation was Strain 1 at lower passage numbers. Furthermore, H295R proliferation increased following Angio II stimulation. In Chapter 5, the hypothesis that increases in miR-125a-5p or miR-335-5p reduces HMGCR and CYP11B2 expression was tested using realtime quantitative RT-PCR and transfection of miRNA mimics and inhibitors into the H295R cell line model of adrenocortical function. In this way, miR-125a-5p and miR-335-5p were shown to downregulate CYP11B2 and HMGCR expression, thereby validating certain of the bioinformatic predictions generated in Chapter 3. The study of miRNA profile in the H295R cell lines was conducted in Chapter 6, analysing how it changes under conditions that increase aldosterone secretion, including stimulation Angiotensin II, potassium chloride or dibutyryl cAMP (as a substitute for adrenocorticotropic hormone). miRNA profiling identified 7 miRNAs that are consistently downregulated by all three stimuli relative to basal cells: miR-106a-5p, miR-154-3p, miR-17-5p, miR-196b-5p, miR-19a-3p, miR-20b- 5p and miR-766-3p. These miRNAs include those derived from cluster miR-106a- 5p/miR-20b-5p and cluster miR-17-5p/miR-19a-3p, each producing a single polycistronic transcript. IPA bioinformatic analysis was again applied to identify experimentally validated and predicted mRNA targets of these miRNAs and the key biological pathways likely to be affected. This predicted several interactions between miRNAs derived from cluster miR-17-5p/miR-19a-3p and important mRNAs involved in cholesterol biosynthesis: LDLR and ABCA1. These predictions were investigated by in vitro experiment. miR-17-5p/miR-106a-p and miR-20b-5p were found to be consistently downregulated by stimulation of aldosterone biosynthesis. Moreover, miR-766-3p was upregulation throughout. Furthermore, I was able to validate the downregulation of LDLR by miR-17 transfection, as predicted by IPA. In summary, this study identified key miRNAs that are differentially-expressed in vivo in cases of APA or in vitro following stimulation of aldosterone biosynthesis. The many possible biological actions these miRNAs could have were filtered by bioinformatic analysis and selected interactions validated in vitro. While direct actions of these miRNAs on steroidogenic enzymes were identified, cholesterol handling also emerged as an important target and may represent a useful point of intervention in future therapies designed to modulate aldosterone biosynthesis and reduce its harmful effects.

Pathogenetic mechanisms of gastrointestinal symptoms in a mouse model of Fabry disease: insights on the microbiota-gut-brain axis

Fabry disease (FD), X-linked metabolic disorder caused by a deficiency in α-galactosidase A activity, leads to the accumulation of glycosphingolipids, mainly Gb3 and lyso-Gb3, in several organs. Gastrointestinal (GI) symptoms are among the earliest and most common, strongly impacting patients’ quality of life. However, the origin of these symptoms and the exact mechanisms of pathogenesis are still poorly understood, thus the pressing need to improve their knowledge. Here we aimed to evaluate whether a FD murine model (α-galactosidase A Knock-Out) captures the functional GI issues experienced by patients. In particular, the potential mechanisms involved in the development and maintenance of GI symptoms were explored by looking at the microbiota-gut-brain axis involvement. Moreover, we sought to examine the effects of lyso-Gb3 on colonic contractility and the intestinal epithelium and the enteric nervous system, which together play important roles in regulating intestinal ion transport and fluid and electrolyte homeostasis. Fabry mice revealed visceral hypersensitivity and a diarrhea-like phenotype accompanied by anxious-like behavior and reduced locomotor activity. They reported also an imbalance of SCFAs and an early compositional and functional dysbiosis of the gut microbiota, which partly persisted with advancing age. Moreover, overexpression of TRPV1 was found in affected mice, and partial alteration of TRPV4 and TRPA1 as well, identifying them as possible therapeutic targets. The Ussing chamber results after treatment with lyso-Gb3 showed an increase in Isc (likely mediated by HCO3- ions movement) which affects neuron-mediated secretion, especially capsaicin- and partly veratridine-mediated. This first characterization of gut-brain axis dysfunction in FD mouse provides functional validation of the model, suggesting new targets and possible therapeutic approaches. Furthermore, lyso-Gb3 is confirmed to be not only a marker for the diagnosis and follow-up of FD but also a possible player in the alteration of the FD colonic ion transport process.

Computational investigation of a stereoselective synthesis of atropisomeric hydrazides possessing an N–N stereogenic axis

Axially chiral substrates are an interesting and widely studied class of compounds as they can be found in bioactive natural products and are employed as functional materials or as ligands in asymmetric catalytic processes. One branch of this family is the well-known world of the atropisomers. Among them, atropisomeric compounds possessing an N–N stereogenic axis are one truthfully fascinating system but not completely understood yet. In this thesis, we computationally investigated the mechanism of the diastereoselective formation of the N – N chiral axis of a hydrazide under asymmetric phase transfer catalytic conditions. Moreover, during this study, torsional barriers have been calculated for both the reagent and the product at the density functional theory (DFT). These values turned out to suitably match the experimental values and observations. Finally, Electronic Circular Dichroism (ECD) spectra have been simulated in order to assign the chiral absolute configuration to the products.