Vnn1 est une pantéthéinase participant à la gestion du stress tissulaire. L’activité pantéthéinase lyse la pantétheine, intermédiaire métabolique dans la synthèse du coenzyme A en cystéamine et pantothénate. Vnn1 est inductible sur des fibroblastes activés et participe à la réparation vasculaire en réponse à l'hypoxie. L’objectif de cette thèse est de déterminer le rôle de Vnn1 dans deux pathologies liées à des dysfonctions myofibroblastiques : la sclérodermie et le fibrosarcome. Dans le cadre d’une collaboration, nous avons montré que Vnn1 est induite sur des fibroblastes sclérodermiques chez la souris et chez l’homme. Des souris Vnn1-/- développent une forme atténuée de la pathologie, avec une réduction de la fibrose et de l’inflammation. Vnn1 pourrait être un marqueur pronostique des formes graves en pathologie humaine. En parallèle, nous avons montré que Vnn1 est exprimée au cours du développement de fibrosarcomes dans un modèle de souris Ink4a/Arf-/-, et se comporte comme un gène suppresseur de tumeur dans ce modèle. Nous avons produit des lignées fibroblastiques Ink4a/Arf-/- qui ont été transformées avec RasV12 en présence de Vnn1 active ou pas. Après greffe, ces lignées produisent des fibrosarcomes. En présence de Vnn1 active, la croissance tumorale est réduite et leur état de différenciation maintenu. De plus, la présence de Vnn1 semble réduire la transition métabolique induite par effet Warburg, amplifiant la glycolyse aérobie et limitant l’activité mitochondriale. Ces résultats montrent que Vnn1 corrèle avec un état activé du myofibroblaste, ce qui est délétère dans le cas de la sclérodermie mais limite la progression tumorale dans le cas des fibrosarcomes. / Vanin-1 (Vnn1) is a pantetheinase which participates in the control of tissue stress. Pantetheinases hydrolyse pantetheines, metabolic intermediates in the synthesis of coenzyme A into cysteamine and pantothenate. Vnn1 is inducible in activated fibroblasts and participates in vascular repair during responses to hypoxic stress. The aim of this thesis was to determine the role of Vnn1 in two pathologies linked to myofibroblasts dysfunction : scleroderma and fibrosarcoma. A collaborative work, have shown that Vnn1 is upregulated in sclerodermic fibroblasts in mouse and in human. Mice Vnn1-/- developed less severe pathology, with a diminution of fibrosis and inflammation. Vnn1 could be a prognostic marker for the severe form of scleroderma. In parallel, we have shown that Vnn1 is expressed during fibrosarcoma development in Ink4a/Arf-/- mice and acts as a tumor suppressor gene in this model. We have generated fibroblastic Ink4a/Arf-/-cell lines which were transduced with RasV12, in presence of a Vnn1 active or not. After engraftment, these cells induced fibrosarcoma. In the presence of the active form of Vnn1, their differentiation into myofibroblasts was maintained and tumor growth was reduced. Moreover, Vnn1 appeared to diminish the metabolic transition induced by the Warburg effect which amplifies aerobic glycolysis, while limiting mitochondrial activity, beneficial for tumor growth. Together, these results show that Vnn1 expression correlates with an activated state of myofibroblasts, which is deleterious in scleroderma but susceptible to limit tumor growth and specifically the development of undifferentiated aggressive fibrosarcoma.

Thesis advisor: David Karp / This project focuses on a case study of a woman with the rare autoimmune disease Scleroderma. It is supplemented with data from in-person interviews and online support groups. The study explores the way a chronic illness (particularly, Scleroderma) impacts elements of identity. / Thesis (BA) — Boston College, 2013. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Sociology Honors Program. / Discipline: Sociology.

Introdução: O Questionário de Avaliação de Saúde em Esclerodermia (SHAQ) é uma ferramenta clínica que avalia especificamente os diversos sistemas acometidos por esta doença. Este instrumento tem sido amplamente utilizado como uma avaliação adicional para a Esclerose Sistêmica (ES). Objetivo: Adaptar culturalmente e validar a versão brasileira do SHAQ. Métodos: A validade de construção foi avaliada com base nas correlações entre SHAQ e o questionário genérico de qualidade de vida Medical Outcome Study Short From-36 (SF-36v2TM) e do índice de incapacidade - HAQ-DI (do inglês, HAQ disatibily index). A correlação entre o SHAQ e gravidade da doença foi avaliada pelo coeficiente de correlação de Spearman. A reprodutibilidade do SHAQ foi avaliada pelo Coeficiente de Correlação Intraclasse (ICC). Resultados: Entre os 151 pacientes consecutivamente avaliados no ambulatório, 59% eram do subtipo limitado de ES. A Escala Visual Analógica (EVA) de avaliação global de doença, que compõe o SHAQ, apresentou correlação estatisticamente significativa com HAQ-DI, EVA de dor e o escore Sumário dos Componentes Físicos (PCS) que compõem o SF-36v2TM (r=0,595, r=0,612, r=-0,582, respectivamente, p<0,001). Uma análise mais aprofundada revelou correlação significativa entre EVA de gravidade de doença e os seguintes componentes do SF-36v2TM: dor corporal (r=-0,621, p<0,001), vitalidade (r=-0,544, p<0,001), capacidade funcional (r=-0,510, p<0,001) e aspecto físico (r=-0,505, p<0,001). Além disso, a EVA digestiva, pulmonar e de avaliação global de gravidade de doença foram correlacionadas com o número de órgãos envolvidos (r=0,178, p=0,029; r=0,214, p=0,008; r=0,282, p<0,001). A reprodutibilidade do SHAQ também foi demonstrada (ICC:0,757, 95% (IC=0,636-0,842). Conclusão: A versão brasileira do SHAQ demonstrou ter validade de construção e discriminante, bem como uma boa reprodutibilidade / Background: The Scleroderma Health Assessment Questionnaire (SHAQ) is a feasible multisystem specific tool that has been extensively used as an additional assessment for systemic sclerosis (SSc). Aims: To cross-culturally adapt and validate the Brazilian Portuguese version of the SHAQ. Methods: Construct validity was assessed based on the correlations between SHAQ and both the Medical Outcomes Survey Short Form 36 version 2 (SF-36v2TM) and the HAQ-DI. The correlation between the SHAQ and disease severity was assessed by Spearman´s correlation coefficient. The reproducibility of the SHAQ was evaluated by intra-class correlation coefficient (ICC). Results: Among the 151 consecutive outpatients evaluated, 59% had limited SSc subtype. The overall disease severity visual analogue scale (VAS) of the SHAQ was statistically significant correlated to HAQ-DI, pain VAS and the SF-36v2TM physical component summary (PCS) score (r=0.595; r=0.612; r=-0.582, respectively; p<0.001). Further analysis of all SF-36v2TM components revealed statistically significant correlations between overall disease severity VAS and bodily pain (r=0.621, p<0.001), vitality (r=-0.544, p<0.001), physical function (r=-0.510, p<0.001) and role limitation-physical dimensions (r=-0.505, p<0.001). Moreover, digestive, pulmonary and overall disease severity VAS were statistically significant correlated to the number of organs involved (r=0.178, p=0.029; r=0.214, p=0.008; r=0.282, p<0.001). We also demonstrated high reproducibility for SHAQ (ICC:0.757, 95% (CI=0.636-0.842). Conclusion: The Brazilian-Portuguese version of the SHAQ demonstrated both construct and discriminant validity, as well as good reproducibility

The management of chronic diseases is described as the “health challenge of the 21st century” by the World Health Organization. Patients’ active role in managing their illness is considered, by many, as central in addressing this challenge. This study explored and described, through scleroderma patients’ own perceptions and understanding, their commitment to illness management, including how they were involved in dealing with their illness and how they learned to do so. The role of social interactions, in particular, support groups, in this process was also investigated. Using a mixed-methods approach, 201 patients were surveyed, and 25 in-depth interviews were conducted. The quantitative results of this study indicated that 64% of patients were committed in managing their illness by being highly active in dealing with their illness. An increase in activation was associated with longer disease duration in the first decade of illness. Additionally, the patients with high social support were more active. The qualitative findings showed patients engaged with various types of work to mitigate the physical, emotional, psychological, relational, and financial impact of the illness. In doing so, patients employed four problem-solving strategies that they had learned by confronting problems in daily lives. These strategies were at the heart of their incidental and tacit learning of how to manage their illness. Only 32% of patients participated in support groups. Support group participants showed higher activation and considered these groups as providing support, learning opportunities, and venues to help other patients. This study indicates that patients’ commitment to management of their illness, far from being a static characteristic of patients, is a spectrum where patients are engaged in a process of complex negotiation with multiple needs of their illness, in tandem with their illness trajectory. Illness uncertainty, learning, and strategies to solve problems in managing the illness frame patients’ commitment and engagement. A preliminary model delineating these elements is provided.

Introduction: Digital ulcers (DUs) are responsible for much of the pain and disability associated with systemic sclerosis (SSc), and are a biomarker of internal organ involvement and poor prognosis. DUs are often used as the primary end-point in SSc clinical trials, although the reliability of rheumatologists in grading DUs is poor to moderate at best. Fingertip DUs are believed to be ischaemic in aetiology, whereas, extensor DUs are thought to occur due to mechanical factors and recurrent microtrauma. Treatments for DUs are often poorly tolerated due to systemic vasodilation. The overarching aim was to investigate the definition and objective measurement of SSc-related DUs, their pathophysiology, and a new light treatment. Method: Five studies were undertaken. (1) A web-based study in which photographs of digital lesions were graded, all either with or without clinical context. (2) A pilot study to assess the feasibility and tolerability of high-frequency ultrasound (HFUS) imaging to measure DUs. (3) A retrospective study examining whether thermographic abnormalities are associated with DUs. (4) A double-blind, randomised, crossover, controlled study of glyceryl trinitrate (GTN) to explore the pathophysiology of DUs in SSc. (5). A feasibility study of a novel light (red, infrared and blue) device to treat SSc-related DUs. Results: (1) 51 rheumatologists graded ≥ 4500 images. The clinical context (without vs with, weighted kappa statistic) did not significantly improve the intra- (0.32,0.36) or inter-rater (0.64,0.71) reliability. (2) HFUS was performed on 15 DUs and was well tolerated and feasible in the majority. DU measurement was possible in most (n=13) DUs, the mean DU depth and width were 0.99mm and 5.74mm, respectively. (3) Patients (n=138) with abnormal (compared to normal) thermography were more likely (adjusted odds ratio = 2.84) to develop future DUs, including multiple episodes. (4) 16 DUs were studied; the microvessels of the DU centre were responsive to GTN, with an increase in perfusion, with a similar effect in both fingertip and extensor DUs. There was less of a clear signal in the DU periphery. (5) Light treatment was safe, feasible and well tolerated (46 light treatments administered in 8 patients, one studied on three separate occasions). There was a significant improvement (change in visual analogue score per visit) in DUs as assessed by both patient (-7.1, P = < 0.001) and clinician opinion (-5.2, P = < 0.001). DU perfusion (measured by LDI) significantly increased post-treatment. Conclusion: The reliability of DU grading did not improve with clinical context. HFUS was feasible and well tolerated, and measurement was possible in most DUs. Our data suggests that many DUs might have an ischaemic drive, including extensor DUs. A novel light treatment was safe, feasible and well tolerated, with a tentative suggestion of treatment efficacy.

Introdução: O Questionário de Avaliação de Saúde em Esclerodermia (SHAQ) é uma ferramenta clínica que avalia especificamente os diversos sistemas acometidos por esta doença. Este instrumento tem sido amplamente utilizado como uma avaliação adicional para a Esclerose Sistêmica (ES). Objetivo: Adaptar culturalmente e validar a versão brasileira do SHAQ. Métodos: A validade de construção foi avaliada com base nas correlações entre SHAQ e o questionário genérico de qualidade de vida Medical Outcome Study Short From-36 (SF-36v2TM) e do índice de incapacidade - HAQ-DI (do inglês, HAQ disatibily index). A correlação entre o SHAQ e gravidade da doença foi avaliada pelo coeficiente de correlação de Spearman. A reprodutibilidade do SHAQ foi avaliada pelo Coeficiente de Correlação Intraclasse (ICC). Resultados: Entre os 151 pacientes consecutivamente avaliados no ambulatório, 59% eram do subtipo limitado de ES. A Escala Visual Analógica (EVA) de avaliação global de doença, que compõe o SHAQ, apresentou correlação estatisticamente significativa com HAQ-DI, EVA de dor e o escore Sumário dos Componentes Físicos (PCS) que compõem o SF-36v2TM (r=0,595, r=0,612, r=-0,582, respectivamente, p<0,001). Uma análise mais aprofundada revelou correlação significativa entre EVA de gravidade de doença e os seguintes componentes do SF-36v2TM: dor corporal (r=-0,621, p<0,001), vitalidade (r=-0,544, p<0,001), capacidade funcional (r=-0,510, p<0,001) e aspecto físico (r=-0,505, p<0,001). Além disso, a EVA digestiva, pulmonar e de avaliação global de gravidade de doença foram correlacionadas com o número de órgãos envolvidos (r=0,178, p=0,029; r=0,214, p=0,008; r=0,282, p<0,001). A reprodutibilidade do SHAQ também foi demonstrada (ICC:0,757, 95% (IC=0,636-0,842). Conclusão: A versão brasileira do SHAQ demonstrou ter validade de construção e discriminante, bem como uma boa reprodutibilidade / Background: The Scleroderma Health Assessment Questionnaire (SHAQ) is a feasible multisystem specific tool that has been extensively used as an additional assessment for systemic sclerosis (SSc). Aims: To cross-culturally adapt and validate the Brazilian Portuguese version of the SHAQ. Methods: Construct validity was assessed based on the correlations between SHAQ and both the Medical Outcomes Survey Short Form 36 version 2 (SF-36v2TM) and the HAQ-DI. The correlation between the SHAQ and disease severity was assessed by Spearman´s correlation coefficient. The reproducibility of the SHAQ was evaluated by intra-class correlation coefficient (ICC). Results: Among the 151 consecutive outpatients evaluated, 59% had limited SSc subtype. The overall disease severity visual analogue scale (VAS) of the SHAQ was statistically significant correlated to HAQ-DI, pain VAS and the SF-36v2TM physical component summary (PCS) score (r=0.595; r=0.612; r=-0.582, respectively; p<0.001). Further analysis of all SF-36v2TM components revealed statistically significant correlations between overall disease severity VAS and bodily pain (r=0.621, p<0.001), vitality (r=-0.544, p<0.001), physical function (r=-0.510, p<0.001) and role limitation-physical dimensions (r=-0.505, p<0.001). Moreover, digestive, pulmonary and overall disease severity VAS were statistically significant correlated to the number of organs involved (r=0.178, p=0.029; r=0.214, p=0.008; r=0.282, p<0.001). We also demonstrated high reproducibility for SHAQ (ICC:0.757, 95% (CI=0.636-0.842). Conclusion: The Brazilian-Portuguese version of the SHAQ demonstrated both construct and discriminant validity, as well as good reproducibility

La sclérodermie systémique (ScS) est une maladie qui peut engager le pronostic vital des malades de façon très rapide. La pathogénie de la maladie reste encore obscure mais est liée aux atteintes vasculaires probablement en lien avec la fibrose cutanée. La thérapeutique de cette maladie est difficile. Aucun traitement étiologique n'existe et la prise en charge est plutôt axée sur les traitements des différentes atteintes. La iontophorèse cutanée est un dispositif qui permet la diffusion de molécules en solution à travers la peau grâce à une stimulation électrique de manière non invasive. Cette technique a été utilisée initialement comme test physiologique. Notre objectif est d'évaluer et de développer la iontophorèse thérapeutique, notamment avec des molécules vasodilatatrices, pour pouvoir l'utiliser dans des applications thérapeutiques telles que la pris en charge des ulcérations digitales (ou troubles trophiques cutanés) de la ScS. Trois parties ont été développées. La première partie consiste en l'association de deux molécules vasodilatatrices (une per os, le sildenafil, et en iontophorèse, le nitroprussiate de sodium (SNP), en étudiant la tolérance de l'association et son effet sur le flux vasculaire cutané chez le volontaire sain (étude INFLUX-VS). La deuxième partie correspond à un screening de molécules ayant une action vasodilatatrice et étant délivrées en iontophorèse chez le rat : l'étude INFLUX-RAT conclue à l'obtention d'une vasodilatation cutanée chez le rat avec les analogues de la prostacycline. La troisième partie correspond à l'évaluation chez le volontaire sain de la iontophorèse des analogues de la prostacycline : l'étude INFLUX-IT-VS conclue à une dilatation du flux sanguin cutané avec le tréprostinil et avec une bonne tolérance cutanée et systémique. La dernière partie correspond aux avancées parallèles des travaux tant dans le domaine de la reproductibilité des techniques d'acquisition des signaux du flux sanguin cutané que les études réalisées avec les patients sclérodermiques à qui on pourrait espérer un jour voir proposer une iontophorèse thérapeutique. / Systemic scleroderma (ScS) is a rare disease that may be associated with a poor prognosis. The pathogenesis of the disease remains still unclear but comprises vascular abnormalities related to skin fibrosis. ScS disease treatment is difficult. No etiologic therapy is available and patient's management is rather centred on the treatments of the different organs failure symptoms. Skin iontophoresis is a non invasive technique, which allows a transcutaneous diffusion of molecules in solution thanks to an electrical stimulation. This technique was initially used as physiological test. Our objective is to test and to develop therapeutic iontophoresis, in particular with molecules possessing vasodilator properties. The final objective is to use it in therapeutic applications such as the treatment of ScS digital ulcerations. Three parts will be developed in the present work. The first part describes the association of two vasodilatator drugs (sildenafil used per os, associated with sodium nitroprusside used through cathodal iontophoresis. We studied the safety of the association and its effect on the skin vascular flow in healthy volunteers (INFLUX-VS study). The second part describes the screening of vasodilatator drugs delivered through cutaneous iontophoresis in rats (INFLUX-RAT study). The aim of the study was to select the more potent drugs in term of maximal rat skin vasodilatation. The more potent drugs were prostacyclins analogues. The third part describes the iontophoresis of prostacyclins analogues in healthy volunteers: the INFLUX-IT-VS study. The more potent cutaneous vasodilatation was observed with treprostinil, with a good skin and systemic tolerance. The last part decribes the reproducibility of the techniques used to quantify skin blood flow along with studies using these techniques in scleroderma patients. These are required to enable a reproducible evaluation of the effect of skin iontophoresis in patients with scleroderma

Thesis (Ph. D.)--University of Missouri-Columbia, 1998. / Typescript. Vita. Includes bibliographical references (leaves 182-210). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 1998. / Typescript. Vita. Includes bibliographical references (leaves 182-210). Also available on the Internet.

Submitted by Nathália Faria da Silva (nathaliafsilva.ufv@gmail.com) on 2017-06-12T11:15:41Z No. of bitstreams: 1 resumo.pdf: 151322 bytes, checksum: 3eefcd9eeadd69fdcb468d564667b9f2 (MD5) / Made available in DSpace on 2017-06-12T11:15:41Z (GMT). No. of bitstreams: 1 resumo.pdf: 151322 bytes, checksum: 3eefcd9eeadd69fdcb468d564667b9f2 (MD5) Previous issue date: 2001-03-12 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Com o objetivo de caracterizar as ectomicorrizas da nogueira pecã, Carya illinoinensis, foram realizadas coletas de basidiocarpos e dos sistemas radiculares em dois plantios experimentais localizados no Campus da UFV e na Fazenda Experimental de Araponga, MG. Basidiocarpos foram encontrados e coletados somente na área do Campus da UFV, provavelmente devido à época de coleta. A partir dos basidiocarpos, foram obtidos 4 isolados de características culturais similares. Estes basidiocarpos foram caraterizados e identificados como pertencentes a Scleroderma verrucosum. Nas duas áreas de plantio de C. illinoinensis, um único morfotipo de ectomicorriza foi observado com as seguintes características: cor branca amarelada, 00-20-00 %CYM; ramificação pinada irregular; hifas da superfície do manto organizados em “net prosenchyma” e as internas organizadas em “net sinenchyma”; rede de Hartig presente viiformando-se intercelularmente a epiderme da raiz e a primeira camada de células do córtex e, eventualmente, a segunda; rizomorfos presentes em grande quantidade apresentando hifas com anastomoses. As ectomicorrizas coletadas no Campus da UFV foram formadas pelo S. verrucosum. Esta identificação foi possível após a constatação da união das ectomicorrizas encontradas, por meio de rizomorfos, a basidiocarpos coletados no local. As ectomicorrizas coletadas na fazenda de Araponga possivelmente foram formadas por S. verrucosum, dado o alto grau de similaridade nas características avaliadas. A porcentagem de micorrização em C. illinoinensis variou de 15 a 32,5 %. O DNA extraído de 3 isolados de S. verrucosum foi amplificado utilizando-se 16 oligonucleotídeos iniciadores e por eletroforese em gel de agarose 1,2%. Foram identificados 84 fragmentos polimórficos e, com base na presença ou ausência destes fragmentos, as distancias genéticas calculadas variaram de 16,8 % a 67 %, demonstrando existir uma grande variabilidade genética entre os isolados fúngicos de uma mesma área. / Aiming at the characterization of C. illinoinensis ectomycorrhizae, fungal basidiocarps and the root system of C. illinonensis were collected in two orchards in the region of Viçosa, one at the campus of Universidade Federal de Viçosa and another at Araponga. Basidiocarps could only be found and collected in the campus orchard probably because of the sampling time (February and July). Four isolates with similar cultural characteristics were obtained from basidiocarps which were characterized and identified as Scleroderma verrucosum. In the two orchards planted with C. illinonensis, a single ectomycorrhizal morphotype was observed that presented the following characteristics: yellowish white color 00-20-00 %CYM; irregular pinate branching; outer mantle hyphae forming a net prosenchyma and inner hyphae a net synenchyma; Hartig net present, penetrating root epidermis, the first, and, ixeventually, the second cell layer of the root cortex; rhizomorphs present in abundance and containing anastomosing hyphae. The ectomycorrhizae found in the campus orchard were formed by S. verrucosum. This was established by examining the connection between the basidiomes present in the sampling site and the ectomycorrhizae, by means of rhizomorphs. Considering the high degree of similarity of the morphological characteristics studied, the ectomycorrhizae sampled at Araponga were probably formed by S. verrucosum. Ectomycorrhizal colonization percentages for 16 cultivars of C. illinonensis varied from 15 to 32.5%, being not statistically different. DNA extracted from 3 isolates of S. verrucosum was amplified using 16 different oligonucleotide primers and were analyzed by electrophoresis in a 1.2% agarose gel. Eighty-four polymorphic amplified fragments were identified and the pairwise genetic distances calculated. The genetic distances varied from 16.8 to 67%, demonstrating the existence of high genetic variability among isolates from a single area.