No / High personal UVR doses can be gained during leisure activities, causing intense self-resolving inflammation (sunburn) of unprotected skin. UVR activates release of membrane fatty acids and upregulates their metabolism by cyclooxygenases (COX) and lipoxygenases (LOX) to different eicosanoids. While COX-derived prostaglandin (PG)E2 is a potent mediator of sunburn vasodilatation, LOX-derived 15-hydroxyeicosatetraenoic acid (HETE) and its lipoxin metabolites may contribute to sunburn limitation. We explored the relationships between expression of these lipid mediators and the clinical and histological outcomes, comparing responses of individuals prone and more resistant to sunburn. An acute UVR exposure of 12 SED (standard erythema dose) was applied to buttock skin of 32 white Caucasians (n = 16 phototype I/II, n = 16 phototype III/IV), and over the subsequent 72 h assessments were made of skin erythema, immunohistochemical expression of leukocyte markers, COX-2, 12-LOX, 15-LOX and nitric oxide synthase (NOS), and eicosanoid levels by LC/ESI-MS/MS. Evidence of a significant inflammatory response was seen earlier in phototype I/II with regard to expression of erythema (4h, p < 0.001), neutrophil infiltration (24 h, p = 0.01), epidermal COX-2 (24 h, p < 0.05) and 12-LOX (24 h, p < 0.01), and dermal eNOS (24 h, p < 0.05) proteins, although CD3+ lymphocyte infiltration showed an earlier increase in phototype III/IV (24 h, p < 0.05). Although erythema was equivalent at 72 h in both groups, phototype I/II showed higher PGE2 accompanied by elevated 15-HETE, and a strong positive correlation was seen between these mediators (n = 18, r = 0.805, p = 0.0001). Hence anti-inflammatory eicosanoid 15-HETE may temper the pro-inflammatory milieu in sunburn, having greater influence in those prone to sunburn than those more resistant, given the same high UVR exposure conditions. / The Wellcome Trust

Yes / Eicosanoids play an integral part in homeostatic mechanisms related to skin health and structural integrity. They also mediate inflammatory events developed in response to environmental factors, such as exposure to ultraviolet radiation, and inflammatory and allergic disorders, including psoriasis and atopic dermatitis. This review article discusses biochemical aspects related to cutaneous eicosanoid metabolism, the contribution of these potent autacoids to skin inflammation and related conditions, and considers the importance of nutritional supplementation with bioactives such as omega-3 and omega-6 polyunsaturated fatty acids and plant-derived antioxidants as means of addressing skin health issues. / The Wellcome Trust and BBSRC-DRINC

No / Background: Skin cancer is a major public health concern, and the majority of cases are caused by solar ultraviolet radiation (UVR) exposure, which suppresses skin immunity. Omega-3 (n−3) PUFAs protect against photoimmunosuppression and skin cancer in mice, but the impact in humans is unknown. Objectives: We hypothesized that EPA-rich n−3 PUFA would abrogate photoimmunosuppression in humans. Therefore, a nutritional study was performed to assess the effect on UVR suppression of cutaneous cell-mediated immunity (CMI) reflected by nickel contact hypersensitivity (CHS). Design: In a double-blind, randomized controlled study, 79 volunteers (nickel-allergic women, 22–60 y old, with phototype I or II) took 5 g n−3 PUFA–containing lipid (70% EPA plus 10% DHA) or a control lipid daily for 3 mo. After supplementation, nickel was applied to 3 skin sites preexposed on 3 consecutive days to 1.9, 3.8, or 7.6 J/cm2 of solar-simulated radiation (SSR) and to 3 unexposed control sites. Nickel CHS responses were quantified after 72 h and the percentage of immunosuppression by SSR was calculated. Erythrocyte [red blood cell (RBC)] EPA was measured by using gas chromatography. Results: SSR dose-related suppression of the nickel CHS response was observed in both groups. Photoimmunosuppression appeared less in the n−3 PUFA group than in the control group (not statistically significant [mean difference (95% CI): 6.9% (−2.1%, 15.9%)]). The difference was greatest at 3.8 J/cm2 SSR [mean difference: 11% (95% CI: 0.5%, 21.4%)]. Postsupplementation RBC EPA was 4-fold higher in the n−3 PUFA group than in the control group (mean difference: 2.69% (95% CI: 2.23%, 3.14%), which confirmed the EPA bioavailability. Conclusion: Oral n−3 PUFAs appear to abrogate photoimmunosuppression in human skin, providing additional support for their chemopreventive role; verification of study findings is required.

Yes / Interferon lambda (IFNλ) is important for epidermal defence against viruses. It is produced by, and acts on, keratinocytes, whereas fibroblasts were previously considered to be unresponsive to this type III IFN. Herein we report findings revealing cell type-specific differences in IFNλ signalling and function in skin resident cells. In dermal fibroblasts, IFNλ induced the expression of MxA, a potent antiviral factor, but not other IFN signature genes as it does in primary keratinocytes. In contrast to its effect on keratinocytes, IFNλ did not phosphorylate STAT1 in fibroblasts, but instead activated MAPKs. Accordingly, inhibition of MAPK activation (p38 and p42/44) blocked the expression of MxA protein in fibroblasts but not in keratinocytes. Functionally, IFNλ inhibited proliferation in keratinocytes but not in fibroblasts. Moreover, IFNλ upregulated the expression of TGFβ1-induced collagens in fibroblasts. Taken together, our findings identify primary human dermal fibroblasts as responder cells to IFNλ. Our study shows cutaneous cell type-specific IFN signalling and suggests that IFNλ, whilst important for epidermal anti-viral competence, may also have a regulatory role in the dermal compartment balancing type I IFN-induced inhibition of tissue repair processes.

No / Wound infection is a major clinical problem, yet understanding of bacterial host interactions in the skin remains limited. Microbe-derived molecules, known as pathogen-associated molecular patterns, are recognised in barrier tissues by pattern-recognition receptors. In particular, the pathogen-associated molecular pattern, lipopolysaccharide (LPS), a component of microbial cell walls and a specific ligand for Toll-like receptor 4, has been widely used to mimic systemic and local infection across a range of tissues. Here we administered LPS derived from Klebsiella pneumoniae, a species of bacteria that is emerging as a wound-associated pathogen, to full-thickness cutaneous wounds in C57/BL6 mice. Early in healing, LPS-treated wounds displayed increased local apoptosis and reduced proliferation. Subsequent healing progression was delayed with reduced re-epithelialisation, increased proliferation, a heightened inflammatory response and perturbed wound matrix deposition. Our group and others have previously demonstrated the beneficial effects of 17β-estradiol treatment across a range of preclinical wound models. Here we asked whether oestrogen would effectively promote healing in our LPS bacterial infection model. Intriguingly, co-treatment with 17β-estradiol was able to promote re-epithelialisation, dampen inflammation and induce collagen deposition in our LPS-delayed healing model. Collectively, these studies validate K. pneumoniae-derived LPS treatment as a simple yet effective model of bacterial wound infection, while providing the first indication that oestrogen could promote cutaneous healing in the presence of infection, further strengthening the case for its therapeutic use.

Being the longest-lived rodent, naked mole-rats (NMR; Heterocephalus glaber) are an exceptional model for biogerontological research. However, unlike other rodents, not much is known about their wound healing process. To investigate that, full-thickness wounds were created in the back skin of naked mole rats. Our initial data confirmed that wound closure in NMR skin was achieved primarily by reepithelialization and granulation tissue formation, with only ~26% wound contraction, making them an excellent model to study human cutaneous wound healing. Similar to mice and human skin, changes in wound epithelial tongue included progressive enlargement of wound epithelium, increased proliferation and changes in the expression pattern of epidermal markers including K14, K17, integrin α6 and E-cadherin. Further analysis revealed characteristics of reduced scarring in NMR wounds including low collagen I to III ratio, increased HA expression (HMW) and increased fibronectin expression. Transcriptional profiling of TGFβ isoforms and different pro/anti-inflammatory cytokines revealed a balance in the expression and repression of different cytokines, potentially contributing into reduced scarring. Comparison of RNA-seq data from NMR and human fullthickness wounds revealed a delay in the activation of important biological processes and pathways in NMR skin in response to injury. Further analysis based on cultured human and NMR cells revealed differential regulation of TGFβ signalling pathway between both species. 3-D collagen gel contraction assay revealed that NMR fibroblast showed noticeable contraction but independently of TGFβ treatment, while human fibroblast showed marked increased in gel contraction in the presence of TGFβ. In conclusion, NMR can serve as a very useful model to study human cutaneous wound healing. The reduced scarring in NMR could be a result of multiple factors including HMW-HA, balanced cytokine expression and differential regulation of different TGFβ cytokines as observed in the in vitro studies.

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-06-21T19:30:11Z No. of bitstreams: 1 RaquelFonteles.pdf: 2324366 bytes, checksum: 7839768f7ff6e0756295b82f795ae2bf (MD5) / Made available in DSpace on 2017-06-21T19:30:11Z (GMT). No. of bitstreams: 1 RaquelFonteles.pdf: 2324366 bytes, checksum: 7839768f7ff6e0756295b82f795ae2bf (MD5) Previous issue date: 2016-06-24 / Leishmaniasis are a group of neglected infectious and parasitic diseases, with major repercussions at global and national level. In the State of Maranhao, both the American Cutaneous Leishmaniasis (LTA) and the American Visceral Leishmaniasis (LVA) are endemic and have great prominence at the national scene. Within the state territory, one of the leading regions is the Lençóis Maranhenses National Park - PNLM, whose surroundings have undergone environmental and ecological damage caused by man, resulting from direct and indirect tourism activities. As a result of this process every year are recorded cases, mostly LTA ones. Goals. Facing such reality, this study aimed: to define the epidemiological profile of the LTA between the years 2007 and 2013, taking into account demographic (age and gender), occupational and chronological features of the affected populations (reported cases); to demonstrate through a cartographic tool, a survey of the timeline distribution of cases of LTA; and an interactive map to determine the risk rate for acquisition of LT. It has been also proposed to study the transmission cycle of the disease, based on the identification of species of sandflies, their sources of blood and their Leishmania genus parasites, and additionally determining vector capacity of Lu. Whitmani toward Le. Braziliensis and Le. Amazonians. Methodology. The county of Barreirinhas was selected for this study because it is the main gateway to PNLM. In short, investigation of LTA cases was carried out in SINAN files, comprising all neighborhoods of the county (158), through the cycle 2007-2013, and sandflies collections were held in 62 of these communities. The species were identified taxonomically and females analyzed at the molecular level to research for natural infection by Leishmania, along with the animals that served as a food source. Results. 458 positive cases of LTA were reported between the years 2007 and 2013, predominantly in men from rural areas and farmers. The cases were concentrated in the south central area of the county, all year round. There was some geographic expansion with the emergence of new outbreaks, however, it was observed the persistence of the former areas of occurrence of the disease. As for the risk rates, villages Sítio Barra, Engenho and Manoelzinho were those who were positive for all variables. On the other side, the communities Quebra, Santa Rosa and Fumaça, presented less risk, since almost all the variables studied were negative for these locations. As for the sandflies, 9,853 specimens of 18 species have been collected, all present in extra-domicile (forest) and only 12 occurring in peri-domicile areas. The incidence was higher in areas surrounding dwellings (56.2%) than in extra-domicile environment (43.8%) and females predominated (51.4%) over males (48.6%). The dominant species were Lu. whitmani (53.83%), Lu. longipalpis (25.60%), Lu. Lenti (11.69%), Lu. evandroi (5.50%) and Lu. flaviscutellata (0.87%). Natural infections due to Le. infantum, were found in females captured in peri-domicile in five villages and extra-domicile in other two. The species Lu. longipalpis, vector of Le. Infantum, indicated a positivity rate of 3.7% for this species. While species not considered insect vector of this leishmania, such as Lu. Lenti and Lu. Whitmani, even so presented infection rates of 0.6% and 0.9%, respectively. Rates of natural infection due to Le. braziliensis, were detected in peri-domicile in two locations; while in Lu. Whitmani, considered the vector of this Leishmania species, rate of 0.3% was found. The rate of infection due to Le. amazonensis was 8% for Lu. Flaviscutelata, captured in peri-domicile in two villages and extra-domicile in just one. Lu. whitmani was able to get infected with Le. Braziliensis and Le. Amazonians. Concerning food source hosts, the following were identified: equines (9.0%), human (1.4%), canine (27.4%), rodent (3.3%), fowl (20.9%) and hogs (37.9%). Conclusion. All elements of the epidemiological chain of Leishmaniasis were present within the area of study, both in peri-domicile and extra-domicile areas, which explains the endemic state of the disease in the region. / Introdução. As leishmanioses constituem um grupo de doenças infectoparasitárias negligenciadas, com grande repercussão a nível mundial e nacional. No Estado do Maranhão tanto a Leishmaniose Tegumentar Americana (LTA) como a Leishmaniose Visceral Americana (LVA) são endêmicas e apresentam grande destaque no cenário nacional. Dentro do território maranhense, uma das regiões de destaque é a do Parque Nacional dos Lençóis Maranhenses – PNLM, cujo entorno, tem sofrido danos ambientais e ecológicos gerados pelo homem, em função das atividades diretas e indiretas do turismo. Como resultado desse processo todos os anos são registrados casos, principalmente de LTA. Objetivos. Diante desta realidade, este trabalho objetivou definir o perfil epidemiológico da LTA entre os anos de 2007 e 2013, levando em consideração os fatores demográficos (faixa etária e sexo), ocupacionais e temporais das populações acometidas (casos notificados); demonstrar através de uma ferramenta cartográfica, um mapa da distribuição espaço temporal dos casos de LTA e um mapa interativo para determinação da taxa de risco para aquisição da LT. Também se propôs estudar o ciclo de transmissão da doença, a partir da identificação das espécies de flebotomíneos, de suas fontes de sangue e de seus parasitas do gênero Leishmania, e determinar capacidade vetorial de Lu. whitmani para Le. Braziliensis e Le. Amazonenses. Metodologia. O município de Barreirinhas foi selecionado para esse estudo porque constitui a principal porta de entrada ao PNLM. Em suma, fez-se o inquérito dos casos da LTA nos arquivos do SINAN de todas as localides do município (158), no período de 2007-2013, e realizou-se coletas de flebotómineos em 62 destes povoados. As espécies foram identificadas taxonomicamente e as fêmeas analisadas a nível molecular para pesquisa de infecção natural por Leishmania e dos animais que serviram como fonte alimentar. Resultados. Foram notificados 458 casos positivos de LTA entre os anos de 2007 e 2013 predominando nos homens provenientes da zona rural e lavradores. Os casos estavam concentrados na região centrosul do município, ao longo dos anos. Houve certa expansão geográfica com o surgimento de novos focos, entretanto, foi observada a persistência das antigas áreas de ocorrência da doença. Quanto às taxas de risco, os povoados Barra do Sitio, Engenho e Manoelzinho foram os que apresentaram positividade para todas as variáveis estudadas. Já os povoados Quebra, Santa Rosa e Fumaça, ofereceram menor risco, uma vez que, quase todas as variáveis estudadas deram negativas para essas localidades. Quanto aos flebotomíneos, foram coletados 9.853 exemplares de 18 espécies, todas presentes no extradomicílio (mata) e apenas 12 ocorreram nos peridomicílios. A abundância foi maior no peridomicílio (56,2%) do que no extradomicílio (43,8%) e as fêmeas predominaram (51,4%) sobre os machos (48,6%). As espécies dominantes foram Lu. whitmani (53,83%), Lu. longipalpis (25,60%), Lu. lenti (11,69%), Lu. evandroi (5,50%) e Lu. flaviscutellata (0,87%). As infecções naturais por Le. infantum, foram encontradas em fêmeas capturadas nos peridomicílios de cinco povoados e no extradomicilio de outros dois. A espécie Lu. longipalpis, vetora de Le. infantum, mostrou uma taxa de positividade de 3,7% para esta espécie. Enquanto espécies não consideradas vetoras desta leishmânia, como Lu. lenti e Lu. whitmani mostraram taxas de infecção de 0,6% e 0,9%, respectivamente. A taxa de infecção natural por Le. braziliensis, foi detectada nos peridomicílios de duas localidades; para Lu. whitmani, considerada vetora desta espécie de Leishmania foi encontrada taxa de 0,3%. A taxa de infecção por Le. amazonensis foi de 8% para Lu. flaviscutelata obtidos nos peridomicilios de dois povoados e no extradomicilio de um apenas. Lu. whitmani foi capaz de se infectar com Le. Braziliensis e Le. Amazonenses. Para fonte alimentar foram identificados os seguintes hospedeiros: equino (9,0%), humano (1,4%), cão (27,4%), roedor (3,3%), galinha (20,9%) e porco (37,9%). Conclusão. Todos os elementos da cadeia epidemiológica das leishmanioses estavam presentes na área do presente estudo, tanto no peridomicílio como no extradomicílio, o que explica a situação endêmica da doença na região.

Les carcinomes spinocellulaires cutanés (cSCCs) sont le deuxième type de cancer par ordre de fréquence et sont responsables de 25% des décès dus aux cancers de la peau. Il est donc essentiel de caractériser les mécanismes responsables de la cancérisation de l'épiderme afin de développer de nouveaux traitements. Dans ce contexte, les miRNAs apparaissent comme des cibles de choix pour le développement de futures thérapies anti-tumorales. Toutefois, leur implication dans la physiopathologie des cSCCs est encore peu documentée. Au cours de cette étude, j’ai identifié, par séquençage à haut débit, 112 miRNAs dont l’expression est altérée au cours du développement tumoral dans un modèle murin de carcinogénèse chimique cutanée. J’ai ensuite focalisé mon attention sur le cluster miR-193b/365a et sur miR-708 dont les niveaux diminuent au cours de la progression tumorale, suggérant des fonctions de suppresseurs de tumeur. En accord avec cette hypothèse, l’expression ectopique de ces miRNAs inhibe la prolifération, la survie et la migration de cellules tumorales, alors que le blocage de leur action par des anti-sens stimule ces fonctions cellulaires dans des kératinocytes normaux. L’association d’approches in silico et d’analyses du transcriptome de cellules de cSCC sur-exprimant ces miRNAs m’a permis d’identifier leurs gènes cibles potentiels. J’ai validé KRAS et MAX comme cibles communes de miR-193b et miR-365a, et montré par l’utilisation de siRNAs que la répression de ces cibles mime les effets de ces miRNAs. Ces résultats suggérent que le ciblage de ces gènes pourrait médier en partie les effets suppresseurs de tumeur de miR-193b et de miR-365a dans les cSCCs. / Cutaneous squamous cell carcinomas (cSCCs) are the second most common cancer and are responsible for up to 25% of all skin cancer deaths. It is therefore essential to characterize the mechanisms responsible for epidermis carcinogenesis to develop new treatments. In this context, miRNAs appear to be prime targets for the development of future anti-tumor therapies. However, their involvement in the pathophysiology of cSCCs is still poorly documented. In this study, I identified using Small RNA sequencing, 112 miRNAs whose expression is altered during tumor development in a mouse model of cutaneous two-stage chemical carcinogenesis. Then, I focused my attention on the miR-193b/365a cluster and on miR-708, that are down-regulated during tumorigenesis, suggesting tumor suppressor functions. Consistent with this hypothesis, the ectopic expression of these miRNAs inhibit the proliferation, survival and migration of tumor cells, while blocking their action with antisense oligonucleotides stimulates these cellular functions in normal keratinocytes. Combining in silico target-prediction approaches and transcriptome analyzes of cSCC cells over-expressing these miRNAs, I identified their potential target genes. I validated KRAS and MAX as direct targets of miR-193b and miR-365a, and I showed that repression of these genes using siRNAs mimics the effects of these miRNAs. These results suggest that targeting these genes might mediate, at least in part, the tumor suppressor action of miR-193b and miR-365a in cSCCs.

A prospective, non-randomized observational study involving forty-nine patients undergoing coronary artery bypass surgery (CABG) with a unilateral harvesting of the internal thoracic artery (ITA) was carried out at the Department of Cardiac Surgery, Herzzentrum Dresden University hospital. Using a commercially available industrial-grade RGB camera and normal indoor lighting, the chest wall of the patients was scanned before surgery and in three follow-up measurements. The primary aim of this thesis was to show whether iPPG is sensitive enough to detect global signal changes after a major surgery – CABG in this case – and local signal changes due to the removal of the ITA, the main supply vessel of the chest wall. As a secondary aim, the thesis looked at subgroups of data to show if differences in signal existed between the colour channels of the RGB camera, subdivisions of the thorax and the surgical technique used as well as to show if demographic factors had an impact on signal strength. With mathematical programs developed by the Technical University Dresden, the scanned optical data was transformed into signal to noise ratios (SNR) used in imaging photoplethysmographic (iPPG) studies. The signal data was analysed in R and, based on a stepwise deletion, a multivariable mixed effects model was constructed. Adjusted versions of this model were used for the analysis of the subgroups of the data. Analysis of the data showed a significant decrease of iPPG signal strength after the CABG surgery with a steeper decrease and an attenuated recovery on the side of the ITA harvesting. Even though the signal variations were relatively small, using the models in this thesis, the differences were reliably detected by iPPG. The analysis of the data from the subdivisions of the chest and from patients’ groups determined by the surgical technique showed a caudo-cranial signal gradient on the ITA side twenty-four hours after the surgery and a stronger signal in the Pedicled group within twenty-four hours after the surgery. The latter calculations, however, were based on a possibly biased sample and should be verified using a controlled sample in prospective randomised study designs. Demographic factors showed no significant correlation with iPPG signal strength. iPPG was able to detect relatively small signal variations that could be associated with changes of cutaneous perfusion after major surgery. Future development could lead to non-invasive monitoring devices in the clinical practice of post-surgery care.:1. Introduction 1 1.1. Coronary Artery Bypass Grafting (CABG) 1 1.1.1. Historical Overview 1 1.1.2. Coronary Grafts 3 1.1.2.1. Pedicled vs. Skeletonised Grafts 4 1.2. Plethysmography 5 1.2.1. Air-Displacement Plethysmography (APG) 5 1.2.2. Strain Gauge Plethysmography (SGP) 6 1.2.3. Impedance Plethysmography (IPG) 6 1.2.4. Photoplethysmography (PPG) 7 1.2.5. Imaging Photoplethysmography (iPPG) 8 1.3. Hypothesis and Aim of the Thesis 11 2. Methods 13 2.1. Study Setting and Patients 13 2.2. Camera and Technical Setup 14 2.3. Recording Area and Regions of Interest 15 2.4. Signal Processing 16 2.5. Statistical Analysis 17 3. Results 19 3.1. Descriptive Properties of the Data 19 3.2. Signal Strength in the Three Colour Channels 20 3.3. Choosing a Multilevel Model 21 3.4. The Effect of the Major Surgery on the Signal Strength in the Three Colour Channels 22 3.5. The Effect of the Unilateral Resection of the Internal Thoracic Artery 25 3.6. Results from the Model Fitted to the Data 27 3.7. The Effect of Cofactors 28 3.8. Data from the Subdivisions of the Chest 29 3.9. The Effect of the Surgical Technique 31 4. Discussion 34 4.1. Signal Strength in the Red, Green and Blue Colour Channels 34 4.2. Signal from the Entire Chest Area 36 4.3. Signal from the Subdivisions of the Chest 37 4.4. The Influence of the Surgical Technique on Signal Strength 38 5. Conclusion 39 6. Abstract 41 7. Zusammenfassung 42 8. References 44 9. Appendix 60 10. Acknowledgements 82 11. Resume 83 Anlage 184 Anlage 2 85 / Eine prospektive, nicht randomisierte Studie mit neunundvierzig Patienten geplant für eine koronare Bypassoperation (CABG) mit einseitiger Präparation der Arteria thoracica interna (ITA) wurde im Herzzentrum Dresden, Universitätsklinikum durchgeführt. In einer präoperativen und in drei postoperativen Messungen wurde die Brustwand bei den untersuchten Patienten unter normaler Innenbeleuchtung mit Hilfe einer handelsüblichen, industriellen RGB Kamera untersucht. Das primäre Ziel der Arbeit war zu zeigen, ob iPPG als Messmethode genug Sensitivität besitzt um globale Signal-Veränderungen nach einem großen Eingriff – die CABG in diesem Fall – und lokale Signaländerung nach der Abnahme der ITA, die Hauptversorgungsarterie der Brustwand, zu erkennen. Als sekundäres Ziel der Arbeit war zu eruieren, ob iPPG Signaldifferenzen zwischen den Farbkanälen der RGB Kamera, den Brustwandaufteilungen und den Arten der ITA Präparation sowie nach den demographischen Faktoren detektieren konnte. Die gemessenen Daten wurden unter Verwendung von Eigentumsprogrammen der Technischen Universität Dresden in den, bei plethysmographischen Studien genutzten, Signal zu Geräusch Quotienten (SNR - signal to noise ratios) umgewandelt. Die gewonnenen Signaldaten wurden in R verarbeitet und durch Verwendung der Methode schrittweise Löschung wurde ein multivariables gemischte Effekte Modell erstellt. Angepasste Versionen dieses Modells wurden für die Analyse von Patientensubgruppen verwendet. Die Datenanalyse ergab eine signifikante Abschwächung des Signals nach der CABG, wobei die Thorax-Seite mit der ITA Präparation zeigte, im Vergleich mit der anderen Thorax-Seite, eine stärkere Abnahme und eine gedämpfte Rückbildung der Signalstärke. Obwohl die detektierte Signaländerungen relativ klein waren, sie konnten durch die entwickelten Modelle mittels iPPG zuverlässig detektiert werden. Die weitere Analyse der Daten aus den Brustwandaufteilungen und von Patientensubgruppen definiert nach Präparationsart der ITA zeigte auf der ITA Seite eine caudo-craniale Zunahme der Signalstärke ab vierundzwanzig Stunden und ein stärkeres Signal in der pedikulierten Präparationsgruppe bis vierundzwanzig Stunden nach der Operation. Allerdings, diese letztere Berechnungen wurden auf einem möglicherweise unausgewogenen Muster durchgeführt und sollten dementsprechend auf kontrollierten Mustern in prospektiven randomisierten Studien verifiziert werden. Die demographischen Faktoren hatten keiner signifikanten Korrelation mit der iPPG Signalstärke. Die iPPG war geeignet kleine Signaländerungen assoziiert mit den erwarteten Änderungen der dermalen Perfusion bei einem großen chirurgischen Eingriff zu detektieren. Weitere Entwicklung der Technologie kann die Anwendung dieses nicht-invasive Monitoringsverfahren in der klinischen postoperativen Patientenversorgung ermöglichen.:1. Introduction 1 1.1. Coronary Artery Bypass Grafting (CABG) 1 1.1.1. Historical Overview 1 1.1.2. Coronary Grafts 3 1.1.2.1. Pedicled vs. Skeletonised Grafts 4 1.2. Plethysmography 5 1.2.1. Air-Displacement Plethysmography (APG) 5 1.2.2. Strain Gauge Plethysmography (SGP) 6 1.2.3. Impedance Plethysmography (IPG) 6 1.2.4. Photoplethysmography (PPG) 7 1.2.5. Imaging Photoplethysmography (iPPG) 8 1.3. Hypothesis and Aim of the Thesis 11 2. Methods 13 2.1. Study Setting and Patients 13 2.2. Camera and Technical Setup 14 2.3. Recording Area and Regions of Interest 15 2.4. Signal Processing 16 2.5. Statistical Analysis 17 3. Results 19 3.1. Descriptive Properties of the Data 19 3.2. Signal Strength in the Three Colour Channels 20 3.3. Choosing a Multilevel Model 21 3.4. The Effect of the Major Surgery on the Signal Strength in the Three Colour Channels 22 3.5. The Effect of the Unilateral Resection of the Internal Thoracic Artery 25 3.6. Results from the Model Fitted to the Data 27 3.7. The Effect of Cofactors 28 3.8. Data from the Subdivisions of the Chest 29 3.9. The Effect of the Surgical Technique 31 4. Discussion 34 4.1. Signal Strength in the Red, Green and Blue Colour Channels 34 4.2. Signal from the Entire Chest Area 36 4.3. Signal from the Subdivisions of the Chest 37 4.4. The Influence of the Surgical Technique on Signal Strength 38 5. Conclusion 39 6. Abstract 41 7. Zusammenfassung 42 8. References 44 9. Appendix 60 10. Acknowledgements 82 11. Resume 83 Anlage 184 Anlage 2 85

Nos travaux de thèse se situent à l’interface entre la recherche fondamentale en neuroscience et ses applications cliniques dans le domaine de la chirurgie réparatrice des membres. Nous nous sommes intéressés au Syndrome Douloureux Régional Complexe de type I caractérisé par l’occurrence d’un état douloureux chronique et d’une perte sévère de mobilité segmentaire. Cette affection, dont l’incidence clinique est élevée, reste à ce jour largement incomprise dans ses mécanismes physiopathologiques et les moyens de traitement disponibles sont d’une efficacité limitée. Dans ce cadre, nous avons d’abord développé une méthodologie de traitement non médicamenteux des deux principaux symptômes de l’algodystrophie que sont la douleur chronique et la mobilité articulaire et validé leur efficacité thérapeutique sur une population de patients.La méthode s’appuie sur les propriétés physiologiques des vibrations mécaniques transcutanées et des vibrations tendineuses qui sont de puissants activateurs des mécanorécepteurs cutanés et proprioceptifs musculaires. L’activation isolée ou conjointe de ces deux canaux sensoriels permet tout à la fois de générer une antalgie puissante et durable et d’améliorer de façon significative la mobilité articulaire. Nous avons ensuite recherché les mécanismes responsables de ces effets. L’utilisation d’un modèle de douleur expérimentale nous a alors permis de montrer que la réduction importante et durable de la douleur générée par les vibrations a une origine à la fois tactile et proprioceptive musculaire, et que ses mécanismes d’action affectent à la fois la transmission médullaire des informations nociceptives et leur traitement central. D’un point de vue théorique nos résultats suggèrent que les afférences proprioceptives cutanées et musculaires contribuent au contrôle des phénomènes douloureux et que les flux afférents proprio-tactile contribuent à la préservation des propriétés fonctionnelles des réseaux centraux responsables de la représentation et de la commande du mouvement. / This thesis tends to deal with both the aspects of neuroscience fundamental research and its possible clinical applications in limbs’ reconstructive surgery. We focused our attention on Complex Regional Pain Syndrome Type I characterized by a chronic pain syndrome associated with a severe loss of segmental mobility. This particular disorder, with a high incidence has been to this day ratherly impenetrable regarding its physiological mechanisms, furthermore available treatments have a limited efficiency.For the matter, we first developed a non-drug therapeutic approach targeting toward algodystrophy two mains symptoms, which are chronic pain and articular mobility loss and monitored its efficiency on a patients’ population.The method is based on the physiological properties of both the tendons vibrations and trancutaneous mechanical vibrations, which are powerful activators of skin’s mechanoreceptors and muscular proprioceptive mechanoreceptors. Isolated or concomitant activation of both those sensorial chanels enables a powerful and lasting analgesic effect along with a significant improvement of the articular mobility.Afterwards, we searched for possible mechanisms behind those outcomes. Using an experimental pain model we were able to show that the significant and lasting reduction of pain endured due to the vibrations comes from afferent messages of tactile and muscular proprioceptive origin, acting both on medullar transmission of the nociceptive inputs and their central processing.From a theoretical perspective, our results suggest that cutaneous and muscular proprioceptive afferences are part of the control process of pain phenomenon and, that afferent proprio-tactile flux contribute to maintaining functional properties of central networks in charge of movement representation and command.