The transcription in the eukaryotic cells involves epigenetic regulatory mechanisms that control local and higher-order chromatin remodelling. In the skin, keratinocyte-specific genes are organized into distinct loci including Epidermal Differentiation Complex (EDC) and Keratin type I/II loci. This thesis introduces bioinformatics approaches to analyze multi-level regulatory mechanisms that control skin development and keratinocyte-specific differentiation. Firstly, integration of gene expression data with analyses of linear genome organization showed dramatic downregulation of the genes that comprise large genomic domains in the sweat glands including EDC locus, compared to ii hair follicles, suggesting substantial differences in global genome rearrangement during development of these two distinct skin appendages. Secondly, comparative analysis of the genetic programmes regulated in keratinocytes by Lhx2 transcription factor and chromatin remodeler Satb1 revealed that significant number of their target genes is clustered in the genome. Furthermore, it was shown in this study that Satb1 target genes are lineage-specific. Thirdly, analysis of the topological interactomes of Loricrin and Keratin 5 in hair follicle steam cells revealed presence of the cis- and trans-interactions and lineage specific genes (Wnt, TGF-beta/activin, Notch, etc.). Expression levels of the genes that comprise interactomes show correlation with their histone modification status. This study demonstrates the crucial role for integration of transcription factormediated and epigenetic regulatory mechanisms in establishing a proper balance of gene expression in keratinocytes during development and differentiation into distinct cell lineages and provides an integrated bioinformatics platform for further analyses of the changes in global organization of keratinocyte-specific genomic loci in normal and diseased skin.

Depuis la fin des années 1980, le phénomène de revitalisation culturelle amérindienne observé à l’échelle continentale s’est enraciné au Québec. Ce phénomène panindien, qui se définit entre autres par un mouvement de guérison dit communautaire – c’est- à-dire qui s’organise à l’intérieur-même des communautés (par opposition à ce qui vient de l’extérieur) – est caractérisé par la prise en charge des problèmes sociaux rencontrés par les populations amérindiennes. Par l’analyse du rite de la tente à sudation, une pratique emblématique de la spiritualité panindienne et du mouvement de guérison, ce mémoire explore la dualité des stratégies de relation d’aide qui y sont déployées. Pour ce faire, l’expérience en milieu carcéral et en communauté d’aînés et d’intervenants autochtones a été prise à témoin. L’enquête de terrain révèle ainsi qu’en parallèle avec la fonction de mobilisation sociale et politique associée à la revitalisation culturelle amérindienne, on assiste à une instrumentation du rituel à des fins psychothérapeutiques. Tout en s’inscrivant dans la structure cosmologique commune à plusieurs traditions orales algonquiennes, cet usage particulier de la symbolique du rituel met à jour une vision plus clinique, plus individualisée et plus dépolitisée de la guérison autochtone habituellement revendiqué dans le discours panindien. / Since the end of the 1980’s, the Native cultural revitalization observed in North America has taken hold in Québec. This panindian phenomenon has defined itself through the aboriginal healing movement. In turn, this healing movement has been addressing the numerous social problems encountered by the Native populations both inside and outside of their communities. While connecting these events, this thesis explores, through the study of the sweat lodge ceremony, the duality of the counseling strategies deployed both in the panindian spirituality and the aboriginal healing movement. In this regard, the counseling experience of elders and professionals in prison and in the community reveals that besides the social and political functions usually associated with aboriginal healing, we can observe a psychotherapeutic instrumentation of the sweat lodge ritual. While capturing the cosmological structure of many Algonquian oral traditions, this particular use of the sweat lodge symbolism shows a more clinical, more individualized and more apolitical vision of aboriginal healing than the one that is usually described in the panindian discourse.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O cultivo da melancia em Roraima vem crescendo a cada ano, devido às condições edafoclimáticas favoráveis, entretanto, a adubação com nitrogênio, que pode interferir na produção e qualidade do fruto, não tem sido estudada. Objetivou-se com o presente trabalho avaliar o efeito da aplicação de diferentes doses de nitrogênio sobre o desempenho agronômico e a qualidade da melancia cv. Crimson Sweet. Conduziu-se essa pesquisa na área experimental da Universidade Federal de Roraima, Boa Vista, RR, no período de janeiro a abril de 2010. O delineamento experimental utilizado foi o de blocos inteiramente casualizados com quatro repetições. Os tratamentos consistiram de cinco doses de nitrogênio (50, 100, 150, 200 e 250 kg ha-1) aplicados na forma de uréia de modo convencional. Os resultados mostraram que a produtividade máxima foi de 40.428 kg ha-1 com a dose de 144,7 kg ha-1 de N. Em relação à qualidade dos frutos, o pH obtido da polpa não foi influenciado pelos tratamentos, apresentando média de 5,34. A relação comprimento/diâmetro e a espessura da casca também não sofreram influência dos tratamentos; enquanto a firmeza do fruto, o conteúdo de sólidos solúveis totais (SST), a acidez titulável (AT), conteúdo de açúcares (redutores, não redutores e totais), o teor de ácido ascórbico e a relação SST/AT foram influenciados pelas doses de nitrogênio. / The cultivation of watermelon in Roraima is growing every year due to favorable climate conditions, however, fertilization with nitrogen, which can interfere with the production and fruit quality has not been studied. The objective was to evaluate the effect of different nitrogen doses application on the agronomic performance and quality of watermelon cv. Crimson Sweet. This research was conducted in the field conditions at Universidade Federal de Roraima, Boa Vista, RR, from January to April 2010. The experimental design was randomized blocks with four replications. The treatments consisted of five nitrogen doses (50, 100, 150, 200 and 250 kg ha-1) applied as urea in a conventional manner. The results showed that commercial production of fruits increased to 40,428 kg ha-1, using 144.7 kg ha-1 of N. The quality of watermelon was influenced by the treatments. The pH was not influenced by treatments and averaged 5.34. The length to diameter ratio and shell thickness also were not affected by treatments, while the firmness of the fruit content of soluble solids (TSS), acidity (TA), sugar content (reducing, non reducing and total), the ascorbic acid and TSS / TA were affected by the nitrogen doses.

La peau est un organe qui enveloppe le corps, elle est une barrière naturelle importante et efficace contre différents envahisseurs. Pour le traitement des maladies dermatologiques ainsi que dans l'industrie cosmétique, les applications topiques sur la peau sont largement utilisées. Ainsi beaucoup d'efforts ont été investis dans la recherche sur la peau visant à comprendre l'absorption moléculaire et les mécanismes rendant efficace la pénétration. Cependant, il reste difficile d'obtenir une visualisation 3D de haute résolution combinée à une information chimique- ment spécifique et quantitative dans la recherche sur la peau. La spectroscopie et la microscopie non-linéaire, incluant la fluorescence excitée à 2-photon (TPEF), la diffusion Raman spontanée, la diffusion Raman cohérente anti-Stokes (CARS) et la diffusion Raman stimulée (SRS), sont introduits dans ce travail pour l'identification sans ambiguïté de la morphologique de la peau et la détection de molécules appliquées de façon topique. Plusieurs méthodes quantitatives basées sur la spectroscopie et la microscopie non-linéaire sont proposées pour l'analyse chimique en3D sur la peau artificielle, ex vivo et in vivo sur la peau humaine. De plus, afin de s'adapter aux applications cliniques à venir, un design endoscopique est étudié pour permettre l'imagerie non-linéaires dans les endoscopes flexibles. / Skin is an organ that envelops the entire body, acts as a pivotal, efficient natural barrier to- wards various invaders. For the treatment of major dermatological diseases and in the cosmetic industry, topical applications on skin are widely used, thus many efforts in skin research have been aimed at understanding detailed molecular absorption and efficient penetration mechanisms. However, it remains difficult to obtain high-resolution visualization in 3D together with chemical selectivity and quantification in skin research. Nonlinear spectroscopy and microscopy, including two-photon excited fluorescence (TPEF), spontaneous Raman scattering, coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS), are introduced in this work for unambiguous skin morphological identification and topical applied molecules detection. Sev- eral quantitative methods based on nonlinear spectroscopy and microscopy are designed for 3D chemical analysis in reconstructed skin, ex vivo and in vivo on human skin. Furthermore, to adapt to forthcoming clinical applications, an endoscopic design is investigated to bring nonlin- ear imaging in flexible endoscopes.

In my master’s degree project in Design at Konstfack, completed and presented during the spring semester of 2022, I combine three of my competencies: Applied knowledge in industrial design, textile and pattern construction and textile materials science. The project was carried out in contact with many different actors, in the industrial design field as well as the textile field. 92% of the garments we wash, we wash unnecessarily. Many garments are washed after just one use. Washing less reduces the wear and tear of the fabric. If we extend the life of the garment by one year, we can reduce our carbon footprint by 25%. Sweat is one of the main reasons why we wash, although the whole fabric does not need to be cleaned. Based on the collected user data, the armpit was identified as one of the primary problem areas. I am developing an absorbent patch for the armpit. This product consists of circular textile materials, in symbiosis with function and shape. The product’s imprint is traceable, as well as transparent in manufacturing. With this absorbing patch, I want to contribute to a sustainable change in the fast-fashion industry by affecting design thinking, demand and consumerism. This project focuses on how we can practice washing less, by identifying behavior patterns, material research in textiles and circular design in product development. Last but not least it is a close study of a product category and how it can be developed. Hence the title: VETT. - “common sense”.

Biological markers (i.e., biomarkers) are essential in clinical and epidemiological studies as they may provide mechanistic insights into the developmental origins of disease, as well as improve diagnostic testing and risk assessment for disease prevention. However, major challenges remain due to the lack of rapid yet selective analytical methods for high throughput screening that are also amenable to volume-restricted specimens. This thesis includes two major research themes that take advantage of capillary electrophoresis (CE) separations, including (1) the targeted analysis of urinary iodide and thiocyanate for assessment of nutritional adequacy and tobacco smoke exposures in the population, and (2) the discovery of new biomarkers in sweat specimens that may improve universal newborn screening programs for cystic fibrosis (CF) infants beyond impaired chloride transport. Chapter II examines the prevalence and risk factors associated with iodine deficiency in 24 h urine samples collected from 800 participants across four clinical sites in Canada as part of the Prospective Urban and Rural Epidemiological (PURE) study when using CE with UV detection in conjunction with sample self-stacking. Importantly, regional variations in iodine status were revealed with participants from Quebec City and Vancouver at greater risk for iodine deficiency than Hamilton and Ottawa. Overall, iodine supplement use, thyroxine prescription, urinary sodium excretion, and self-reported dairy intake were found to be protective factors against iodine deficiency. Chapter III applied a validated CE assay to measure urinary thiocyanate as a biomarker of tobacco smoke and dietary exposures in an international cohort of 1000 participants from the PURE study spanning 14 countries with varied income status, smoking habits, and diet quality. Current smokers residing in high-income countries had the highest extent of cyanide exposure indicative of greater harms from tobacco smoke compared to middle- and low-income countries after adjusting for smoking intensity and other covariates. Chapter IV introduces a rapid CE method with indirect UV detection to simultaneously measure sweat chloride and bicarbonate from presumptive CF infants’ residual sweat samples. Although bicarbonate did not provide clinical value in neonatal CF diagnosis, sweat chloride testing by CE may reduce test failure rates due to insufficient volumes from infants in a clinical setting. Lastly, Chapter V applied an untargeted strategy to characterize the sweat metabolome from presumptive CF infants when using multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS). A panel of sweat metabolites were found to discriminate CF from non-CF (i.e., unaffected carriers) infants, including aspartic acid, glutamine, oxoproline, and pilocarpic acid, which also correlated with sweat chloride. The clinical utility of these sweat metabolites to prognosticate late-onset CF infants from indeterminate sweat chloride test results was also explored. In summary, this thesis contributes innovative separation methods for biomarker screening and discovery in clinical and epidemiological studies for the prevention and early treatment of human diseases that benefit from optimal nutrition. / Dissertation / Doctor of Philosophy (PhD)

The transcription in the eukaryotic cells involves epigenetic regulatory mechanisms that control local and higher-order chromatin remodelling. In the skin, keratinocyte-specific genes are organized into distinct loci including Epidermal Differentiation Complex (EDC) and Keratin type I/II loci. This thesis introduces bioinformatics approaches to analyze multi-level regulatory mechanisms that control skin development and keratinocyte-specific differentiation. Firstly, integration of gene expression data with analyses of linear genome organization showed dramatic downregulation of the genes that comprise large genomic domains in the sweat glands including EDC locus, compared to ii hair follicles, suggesting substantial differences in global genome rearrangement during development of these two distinct skin appendages. Secondly, comparative analysis of the genetic programmes regulated in keratinocytes by Lhx2 transcription factor and chromatin remodeler Satb1 revealed that significant number of their target genes is clustered in the genome. Furthermore, it was shown in this study that Satb1 target genes are lineage-specific. Thirdly, analysis of the topological interactomes of Loricrin and Keratin 5 in hair follicle steam cells revealed presence of the cis- and trans-interactions and lineage specific genes (Wnt, TGF-beta/activin, Notch, etc.). Expression levels of the genes that comprise interactomes show correlation with their histone modification status. This study demonstrates the crucial role for integration of transcription factormediated and epigenetic regulatory mechanisms in establishing a proper balance of gene expression in keratinocytes during development and differentiation into distinct cell lineages and provides an integrated bioinformatics platform for further analyses of the changes in global organization of keratinocyte-specific genomic loci in normal and diseased skin.

Einleitung: Die Supplementation von Elektrolyten beim Pferd wird als Risikofaktor für die Entstehung von Magenschleimhautveränderungen postuliert, jedoch liegen hierzu nur unzureichende Untersuchungen beim Pferd vor. Ziele der Untersuchungen: Das Ziel der Studie war die Untersuchung der Effekte einer pelletierten Natriumchlorid (NaCl)-Supplementation auf die Magenschleimhaut, den Säure- Basen- und den Mineralstoffhaushalt bei Sportpferden. Es wurde die Hypothese aufgestellt, dass eine NaCl-Supplementation in einer pelletierten Konfektionierung, dosiert zum Ausgleich von Elektrolytverlusten durch zehn Liter Schweiß, Magenschleimhautveränderungen nicht induzieren bzw. verschlechtern, sowie keinen negativen Effekt auf den Säure-Basen- und Mineralstoffhaushalt bei Sportpferden hervorbringen würde. Material und Methoden: 15 dreijährige, gesunde Warmbluthengste von einem Gestüt wurden im randomisierten Cross-over-Verfahren untersucht. Die Pferde erhielten für 19 Tage entweder ein NaCl-Pellet in einer Dosierung zum Ausgleich von Elektrolytverlusten durch zehn Liter Schweiß oder ein Placebo-Pellet in gleicher Menge. Zwischen den Fütterungsperioden lag eine 14-tägige Wash-out-Periode. Die Magenschleimhaut wurde mittels Gastroskopie vor (T0) und nach jeder Fütterungsperiode (T21) evaluiert. Es wurden Blutproben zur Untersuchung des Säure-Basen-Haushalts, Hämatokrit und Gesamteiweiß-, Kreatinin- und Harnstoffkonzentrationen jeweils vor (T-1) und nach den Fütterungsperioden (T20) entnommen. Spontanharn wurde an denselben Tagen wie die Blutentnahme aufgefangen und es erfolgte die Untersuchung auf das urinspezifische Gewicht und den Elektrolyt-, Kreatinin- und Harnstoffkonzentrationen. Die Ermittlung der Wasseraufnahme über 24-h erfolgte zu definierten Zeitpunkten. Statistik: Die Daten wurden mittels StatSoft STATISTICAÒ und SPSSÒ ausgewertet. Eine Power-Analyse mit einer Power von 0,95 und einem medianen Unterschied von einem Grad an Magenschleimhautveränderungen ergab eine Probengröße von mindestens 14 Pferden. Die Daten wurden auf Normalverteilung überprüft. Normalverteilte Daten wurden mittels ANOVA und Fisher LSD Test und nicht normalverteilte Daten mittels Wilcoxon Test ausgewertet. Das Signifikanzniveau wurde mit p < 0.05 festgelegt. Ergebnisse: Die initiale Prävalenz von Magenschleimhautveränderungen lag bei 83,3 % (Pars nonglandularis: Score 0: 16,66 %, Score 1: 33,33 %, Score >1: 50 %; Pars glandularis: Score 0: 16,66 %, Score 1: 50 %, Score >1: 33,33 %). Die Supplementation der NaCl-Pellets hatte keinen negativen Effekt auf die Magenschleimhaut (Median Score (25./75. Perzentil) z.B. in der großen Kurvatur der Pars nonglandularis (NaCl: T0 = 1 (0/1), T21 = 0 (0/2), p = 0,74; Placebo: T0 = 0 (0/2), T21 = 0 (0/2), p = 0,62) oder im Antrum pyloricum (NaCl: T0 = 1 (1/1), T21 = 1 (1/2), p = 0,43; Placebo: T0 = 1 (1/1), T21 = 2 (1/2), p = 0,1). Der Blut pH-Wert, die Konzentration des Gesamteiweißes und der Hämatokrit zeigten keine signifikanten Veränderungen nach NaCl-Supplementation im Vergleich zum Placebo. Bei den Elektrolyten gab es zeitabhängige Veränderungen, ohne signifikanten Einfluss der NaCl-Supplementation gegenüber dem Placebo. Im Urin wurde die mittlere (± SD) Natrium-Konzentration durch die NaCl-Supplementation signifikant erhöht (NaCl: T-1 = 29,3 ± 15,8 mmol/l, T20= 96,4 ± 61,3 mmol/l, p = 0,01; Placebo: T-1 = 17,5 ± 3,7 mmol/l, T20= 21,8 ± 5,6 mmol/l, p = 0,85) und die mittlere Kreatinin-Konzentration im Urin signifikant erniedrigt. Das urinspezische Gewicht und die Kalzium-Konzentrationen im Urin zeigten eine Erniedrigung über Zeit in beiden Fütterungsgruppen ohne behandlungsbedingte Effekte. Die 24-h Wasseraufnahme wurde durch die NaCl-Supplementation im Vergleich zum Placebo nicht beeinflusst. Schlussfolgerung: Eine tägliche NaCl-Supplementation in der Konfektionierung eines Pellets ist eine schmackhafte und sichere Methode, um Elektrolytverluste durch den Schweiß bei Sportpferden auszugleichen. Die NaCl-Supplementation hatte weder negative Effekte auf die Magenschleimhaut noch auf den Säure-Basen- und Mineralstoffhaushalt bei Pferden.:1. Einleitung 2. Literaturübersicht 2.1. Salzsupplementation bei Pferden 2.1.1. Aufgaben von NaCl im Körper des Pferdes 2.1.2. Auswirkungen einer Unterversorgung mit NaCl 2.1.3. Täglicher Bedarf an NaCl 2.1.4. Verlust von NaCl über den Schweiß des Pferdes 2.1.5. Versorgung mit NaCl durch Futtermittel 2.1.6. NaCl-Supplementation 2.1.6.1. Positive Auswirkungen der Supplementation von Elektrolyten bzw. NaCl bei Sportpferden auf die Rehydratation, die Kompensation von Elektrolytverlusten und Glykogen-Resynthese 2.1.6.2. Effekte einer NaCl-Supplementation auf den Säure-Basen-Haushalt von Pferden 2.1.6.3. Effekte einer NaCl-Supplementation auf den Urin von Pferden 2.1.6.4. Effekte einer NaCl-Supplementation auf den Wasserhaushalt bzw. die Wasseraufnahme von Pferden 2.2. Equine Gastric Ulcer Syndrome 2.2.1. Definition 2.2.2. Prävalenzen von Magengeschwüren 2.2.3. Risikofaktoren 2.3. Auswirkungen einer NaCl-Supplementation auf die Magenschleimhaut 2.3.1. Auswirkungen bei Pferden 2.3.2. Auswirkungen beim Menschen und anderen Tierspezies 3. Publikation 3.1. The effects of feeding sodium chloride pellets on the gastric mucosa, acid-base, and mineral status in exercising horses 4. Diskussion 4.1. Kritik der Methoden 4.2. Diskussion der Ergebnisse 4.3. Fazit 5. Zusammenfassung 6. Summary 7. Literaturverzeichnis 8. Anhang 8.1. Liste der Vorträge im Rahmen dieser Dissertation 9. Danksagung / Introduction: Electrolyte supplementation may be a risk factor for gastric mucosal lesions, but relevant evidence is limited in horses. Aim of the study: The aim of the study was to investigate the effects of a pelleted sodium chloride (NaCl) supplementation on the gastric mucosa, the acid-base and mineral status of exercising horses. We hypothesized that NaCl supplementation in form of a pellet would neither cause nor exacerbate existing gastric mucosal damage and would not have negative effects on the acid-base and mineral status, when fed in a dosage to compensate for electrolyte losses in 10 L of sweat. Material and Methods: This study was a randomized placebo-controlled study in a crossover design. 15 3-year-old healthy Warmblood stallions from a stud farm were fed either a NaCl pellet in a dosage to replace sweat losses of 10 L or a placebo for 19 days with a wash-out period of 14 days between treatments. The gastric mucosa was evaluated by gastroscopy before (T0) and after (T21) treatment. Blood samples were collected for evaluation of acid-base status, packed cell volume and total protein, creatinine and blood urea nitrogen concentrations before (T-1) and after (T20) treatments. Spontaneous urine was collected on the same days as blood was taken for measurements of urine specific gravity, electrolytes, creatinine and urea concentrations. Furthermore, daily water intake was measured. Statistics: Data were processed using StatSoft STATISTICAÒ and SPSSÒ. A power analysis with a power of 0.95 and a median difference of 1 grade of gastric ulceration was performed to estimate the minimum required sample size of 14 animals. The data were analyzed for normal distribution. Normally distributed data were tested for significance using the ANOVA and the Fishers LSD test. If the data were non-parametric, significance was tested by Wilcoxon test. Significance was set at p < 0.05. Results: The initial prevalence of gastric mucosal lesions was 83.3 % (squamous mucosa: score 0: 16.66 %, score 1: 33.33 %, score >1: 50 %; glandular mucosa: score 0: 16.66 %, score 1: 50 %, score >1: 33.33 %). The supplementation of the NaCl pellets did not adversely affect the gastric mucosa (median score (25th/75th percentile); for example, the greater curvature squamous mucosa (NaCl: T0 = 1 (0/1), T21 = 0 (0/2), p = 0.74; placebo: T0 = 0 (0/2), T21 = 0 (0/2), p = 0.62) or the pyloric antrum (NaCl: T0 = 1 (1/1), T21 = 1 (1/2), p = 0.43; placebo: T0 = 1 (1/1), T21 = 2 (1/2), p = 0.1). In the venous blood pH, total protein and PCV did not show any significant differences after NaCl supplementation in comparison to the placebo. The electrolytes showed significant time related differences in both treatment groups, but no significant effect could be seen between NaCl and placebo. Urinary sodium values significantly increased after NaCl supplementation (mean ± SD; NaCl: T-1= 29.3 ± 15.8 mmol/L, T20= 96.4 ± 61.3 mmol/L, p= 0.01; placebo: T-1= 17.5 ± 3.7 mmol/L, T20= 21.8 ± 5.6 mmol/L, p= 0.85). Urinary creatinine values significantly decreased after NaCl supplementation. Urinary specific gravity and urinary calcium concentrations showed a significant decrease in both treatment groups, but without any significant differences between diets. The amount of water intake over 24 h did not differ significantly between diets. Conclusion: Daily NaCl supplementation in form of a pellet is a palatable and safe way to replace electrolyte losses from sweating in exercising horses. A pelleted NaCl supplementation does not have negative effects on neither the gastric mucosa, nor the acid-base and mineral status.:1. Einleitung 2. Literaturübersicht 2.1. Salzsupplementation bei Pferden 2.1.1. Aufgaben von NaCl im Körper des Pferdes 2.1.2. Auswirkungen einer Unterversorgung mit NaCl 2.1.3. Täglicher Bedarf an NaCl 2.1.4. Verlust von NaCl über den Schweiß des Pferdes 2.1.5. Versorgung mit NaCl durch Futtermittel 2.1.6. NaCl-Supplementation 2.1.6.1. Positive Auswirkungen der Supplementation von Elektrolyten bzw. NaCl bei Sportpferden auf die Rehydratation, die Kompensation von Elektrolytverlusten und Glykogen-Resynthese 2.1.6.2. Effekte einer NaCl-Supplementation auf den Säure-Basen-Haushalt von Pferden 2.1.6.3. Effekte einer NaCl-Supplementation auf den Urin von Pferden 2.1.6.4. Effekte einer NaCl-Supplementation auf den Wasserhaushalt bzw. die Wasseraufnahme von Pferden 2.2. Equine Gastric Ulcer Syndrome 2.2.1. Definition 2.2.2. Prävalenzen von Magengeschwüren 2.2.3. Risikofaktoren 2.3. Auswirkungen einer NaCl-Supplementation auf die Magenschleimhaut 2.3.1. Auswirkungen bei Pferden 2.3.2. Auswirkungen beim Menschen und anderen Tierspezies 3. Publikation 3.1. The effects of feeding sodium chloride pellets on the gastric mucosa, acid-base, and mineral status in exercising horses 4. Diskussion 4.1. Kritik der Methoden 4.2. Diskussion der Ergebnisse 4.3. Fazit 5. Zusammenfassung 6. Summary 7. Literaturverzeichnis 8. Anhang 8.1. Liste der Vorträge im Rahmen dieser Dissertation 9. Danksagung

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene (EDA). Most affected males are hemizygous for EDA null mutations that lead to the absence or inactivity of the signalling protein ectodysplasin A1 (EDA1) and, thus, to the full-blown phenotype with inability to perspire and few if any teeth. There are currently no long-term treatment options for XLHED. ER004 represents a first-in-class protein replacement molecule designed for specific, high-affinity binding to the endogenous EDA1 receptor (EDAR). Its proposed mechanism of action is the replacement of missing EDA1 in yet unborn patients with XLHED. Once bound to EDAR, ER004 activates the EDA/NFκB signalling pathway, which triggers the transcription of genes involved in the normal development of multiple tissues. Following preclinical studies, named-patient use cases demonstrated significant potential of ER004 in affected males treated in utero during the late second and third trimesters of pregnancy. In order to confirm these results, we started the EDELIFE trial, a prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration as a prenatal treatment for male subjects with XLHED. This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls.

O tingimento de tecidos começou há milhares de anos e a disponibilidade comercial de corantes é enorme e crescente. A indústria têxtil brasileira desempenha um papel de inquestionável importância, destacando-se entre as principais atividades econômicas do país. O processo de tingimento é um dos fatores fundamentais no sucesso comercial dos produtos têxteis, uma vez que o consumidor exige cores resistentes à exposição ao calor, à luz, à transpiração e às lavagens. Segundo a literatura, condições de transpiração intensa contribuem para uma alta taxa de migração e subseqüente penetração de corantes têxteis para a pele humana. Além disso, 2 a 50% desses compostos permanecem no banho de tingimento e são descartados nos efluentes industriais, contaminando o ambiente e colocando em risco a saúde humana, uma vez que os métodos convencionais de tratamento de efluentes são ineficientes na remoção da coloração e da mutagenicidade de alguns corantes. Dentro deste contexto, este trabalho teve como objetivo avaliar os efeitos toxicogenéticos do corante Direct Black (DB38) original e após extração por lixiviação com suor sintético, utilizando o teste do cometa com fibroblastos e queratinócitos de pele humana, o teste Anexina V com fibroblastos e o ensaio de mutagenicidade com Salmonella typhimurium. Adicionalmente, foi investigada a ecotoxicidade dos corantes têxteis Direct Black 38 e Reactive Blue 15 (RB15) originais por meio de ensaios com sementes, dapnhias, minhocas e zebrafish realizados na UTOX, em Barcelona. O corante DB38 original e lixiviado não induziram genotoxicidade em fibroblastos e queratinócitos de pele humana. O corante DB38 original foi mutagênico para as linhagens TA98 e TA100 de S. typhimurium na presença de S9. Entretanto, o corante lixiviado não induziu mutagenicidade para essas linhagens testadas, considerando que a maior taxa de migração do corante para a solução de suor foi de ~1% nas seguintes condições: tingimento sem ensaboamento, pH 8,0 e 8 horas de incubação à 42°C. O corante original é citotóxico para fibroblastos após 48 horas de exposição. No entanto, essa citotoxicidade não foi mais observada após a lixiviação no suor. Os corantes DB38 e RB15 originais não foram tóxicos para as sementes de pepino, alface e tomate, e nem para as minhocas Eisenia foetida. Ambos os corantes foram fracamente tóxicos para Daphnia magna, porém o RB15 apresenta maior potencial tóxico em relação ao DB38. Os corantes DB38 e RB15 induziram malformações em larvas de zebrafish Danio rerio, caracterizadas por falha na inflação da bexiga natatória e alteração na cauda. Portanto, nossos resultados mostram a importância de se fazer não só a análise individual de corantes têxteis, mas também dos tecidos que os contêm. Além da necessidade de se desenvolver técnicas de tingimento mais seguras em relação à solidez da cor sob condições úmidas e as perdas de corante para o ambiente durante a etapa de fixação, indicando maior atenção ao estudo de efeitos sub-letais na avaliação do impacto desses compostos no ecossistema aquático. / The fabrics dyeing began thousands of years ago and the commercial availability of dyes is increasingly. The Brazilian textile industry plays a role of high importance, highlighting among the main economic activities in the country. The dyeing process is one of the key factors in the commercial success of textile products, since consumers are demanding colors more resistant to heat, light exposure, perspiration and washing. According to the literature, conditions of intense perspiration contribute to the migration and subsequent penetration of textile dyes to human skin. Furthermore, 2 to 50% of the initial dye load is present in the dye bath effluent and these compounds are discharged in industrial effluents, contaminating the environment and endangering human health, since the wastewater treatment systems are ineffective in removing the color and mutagenicity of some dyes. In this context, this study aimed to evaluate the toxicogenetic effects of the Direct Black 38 (DB38) dye original and extracted by leaching with artificial sweat using Comet assay with fibroblasts and keratinocytes from human skin, Anexin V assay with fibroblasts and Salmonella mutagenicity test. Additionally, we investigated the ecotoxicity of textile dye Direct Black 38 and Reactive Blue 15 (RB15) using assays with seeds, dapnhias, worms and zebrafish performed in UTOX in Barcelona. The original and leached DB38 dye did not induce genotoxicity in fibroblasts and keratinocytes from human skin. The original DB38 was mutagenic for TA98 and TA100 of S. typhimurium with S9. However, the solution with the leached dye did not induce mutagenicity for these tested strains, since the highest migration rate of the dye to the solution of artificial sweat was ~ 1% in the following conditions: type of dyeing without rinsing, pH 8.0 and 8-hour incubation at 42°C. The original dye was cytotoxic for fibroblasts after 48 hours of exposure. However, this cytotoxicity was no longer observed after leaching in sweat. The original DB38 and RB15 dyes showed no toxicity for cucumber, lettuce and tomato seeds and for earthworms Eisenia foetida. Both dyes were weakly toxic for Daphnia magna, but the RB15 has a higher toxic potential compared to DB38. The dyes DB38 and RB15 induced malformations in larvae of zebrafish Danio rerio by failure of the swim bladder inflation and changes in the tail. Therefore, our results show the importance of making the individual analysis of textile dyes, but also of fabrics containing them. Furthermore, it is necessary to develop safer techniques of dyeing in relation to the color fastness under humid conditions and the loss of dyes into the environment during the fixation step, indicating more attention to the study of sub-lethal effects in the evaluation of the impact of these compounds in the aquatic ecosystem.