L’évolution du Syndrome Douloureux Régional Complexe (SDRC) peut aboutir à un état de douleur chronique invalidant et difficile à traiter. Parmi les stratégies thérapeutiques utilisables, la kétamine, administrée sur 5 jours à des doses infra-anesthésiques, a une place de choix. Cependant, il s'agit d'un traitement invasif et dont le mécanisme d'action antalgique n'est pas connu. Notre travail a porté sur deux aspects du traitement du SDRC par la kétamine: la prédiction de l’efficacité thérapeutique et la compréhension des mécanismes d'action. Dans un premier temps, chez 105 patients SDRC, nous avons évalué l'intérêt de la scintigraphie osseuse au Technétium 99 réalisée avant le traitement pour prédire l’efficacité thérapeutique de la kétamine. Cette efficacité était corrélée à l’augmentation relative de l'activité inflammatoire et du remodelage osseux objectivée par scintigraphie. Dans une deuxième étude, portant sur l’évaluation de l’excitabilité corticale par stimulation magnétique transcrânienne et incluant 19 patients SDRC, nous avons observé que la kétamine réprimait fortement et de façon bilatérale la facilitation intracorticale, paramètre de transmission glutamatergique, et en revanche restaurait l’inhibition intracorticale correspondant au côté douloureux, paramètre gabaergique qui était très altéré avant le traitement. L'effet antalgique de la kétamine était corrélé à cette restauration d'inhibition ainsi qu'à la réduction de la facilitation correspondant au côté sain. Ainsi, la kétamine semble jouer un rôle dans la balance d'influences gabaergiques et glutamatergiques transcalleuses. Ce travail a permis de caractériser de nouveaux mécanismes physiopathologiques ainsi qu’une nouvelle justification de l’efficacité thérapeutique de la kétamine dans le SDRC. / Regional Complex Pain Syndrome (CRPS) can result in a chronic pain condition that is disabling and difficult to treat. Among the therapeutic strategies that can be used, ketamine, administered over 5 days at infra-anesthetic doses, has a place of choice. However, it is an invasive treatment and the mechanism of analgesic action is not known. Our work focused on two aspects of the treatment of CRPS by ketamine: predicting therapeutic efficacy and understanding mechanisms of action. Initially, in 105 CRPS patients, we assessed the benefit of pre-treatment Technetium 99 bone scintigraphy to predict the therapeutic efficacy of ketamine. This efficacy was correlated with the relative increase in inflammatory activity and bone remodeling detected by scintigraphy. In a second study, evaluating cortical excitability by transcranial magnetic stimulation and including 19 CRPS patients, we observed that ketamine strongly and bilaterally repressed intracortical facilitation, a glutamatergic transmission parameter, and on the other hand restored the intracortical inhibition corresponding to the pain side, a gabaergic parameter which was very altered before the treatment. The analgesic effect of ketamine was correlated with this restoration of inhibition as well as the reduction of the facilitation corresponding to the healthy side. Thus, ketamine seems to play a role in the balance of gabaergic and glutamatergic transcallosal influences. This work allowed new physiopathological mechanisms to be characterized as well as a new justification of the therapeutic efficacy of the ketamine in the CRPS.

A cintilografia renal é um exame amplamente utilizado para a avaliação visual do funcionamento do córtex renal. Ele permite visualizar a concentração do radiofármaco, o tamanho, a forma, a simetria e a posição dos rins. No entanto, a avaliação visual das impressões diagnósticas dessas imagens tende a ser um processo subjetivo. Isso faz com que ocorra uma significativa variabilidade entre as interpretações feitas por diferentes especialistas. Assim, este trabalho tem como objetivo propor medidas quantitativas que refletem impressões diagnósticas comumente observadas por especialistas nas imagens de cintilografia renal. São atribuídos valores numéricos a essas impressões, o que, potencialmente, reduz a subjetividade e a variabilidade da interpretação das descobertas. A fim de permitir a extração dessas medidas, um método de segmentação específico para essas imagens também é proposto. Os resultados indicam que as medidas propostas atingem níveis de concordância de no mínimo 90% dos casos quando comparadas com a avaliação visual de especialistas. Esses resultados sugerem que as medidas podem ser usadas para reduzir a subjetividade na avaliação das imagens, já que elas fornecem uma alternativa quantitativa e objetiva para reportar as impressões diagnosticas das imagens de cintilografia renal. / Renal scintigraphy is a well established functional technique for the visual evaluation of the renal cortical mass. It allows the visualization of the radiopharmaceutical tracer distribution, the size, the shape, the symmetry, and the position of the kidneys. However, the visual diagnostic impressions for these images tend to be a subjective process. It causes significant variability in the interpretation of findings. Thus, this work aims at proposing quantitative measures that reflect common diagnostic impressions for those images. These measures can potentially minimize the inter-observer variability. In order to make possible the extraction of these measures, a specific segmentation method is also proposed. The results indicate that our proposed features agree in at least 90% of the cases with the specialists visual evaluation. These results suggest that the features could be used to reduce the subjectivity in the evaluation of the images, since they provide a quantitative and objective alternative to report the diagnostic impressions.

Introdução: A presença de cálcio nas artérias coronárias identifica a existência de aterosclerose coronariana, mesmo em fases precoces. Por outro lado, a decisão quanto à melhor forma de tratamento dessa entidade baseia-se no uso de exames funcionais, em especial, a cintilografia de perfusão do miocárdio (CPM). Existem dúvidas quanto à correlação desses dois exames, o que poderia ser, ao menos em parte, explicada pelo fato dos testes avaliarem fases distintas dessa entidade. Este estudo pretende avaliar o uso de uma abordagem anatômica e funcional combinada por meio da (CPM) e tomografia computadorizada coronária com multidetectores (TCMD) na determinação do escore de cálcio (CACS) e da presença de estenoses e isquemia e examinar a associação de seus resultados entre si e com outras variáveis demográficas, clínicas e funcionais em uma população brasileira com doença arterial coronária (DAC) suspeita ou conhecida. Métodos: foram analisados, retrospectivamente, 413 pacientes que se submeteram à CPM e TCMD por indicação clínica do médico assistente, durante o ano de 2009, com intervalo menor de 90 dias, entre os dois estudos. CACS foi definido automaticamente pelo software dedicado e o escore de Agatston foi calculado de forma semiquatitativa. Na CPM e na TCMD, os resultados foram obtidos por quantificação visual semiobjetiva. A correlação dos resultados dos exames foi analisada e foram obtidos dados da evolução tardia, baseados no contato com o médico assistente ou pela análise dos registros hospitalares. Procurou-se definir os preditores da ocorrência de eventos cardiovasculares adversos na evolução. Resultados: Foram selecionados 303 pacientes (73,3% homens, média de idade de 55,8 ± 10,6 anos, intervalo: 32-86 anos). Destes, 73,3% apresentaram estudos de perfusão normal, 71,6% tinham cálcio coronário e 45,2% tinha perfusão normal e TCDM com cálcio. No grupo sem suspeita de DAC (177), houve associação entre os resultados de TCMD e SPECT com: diabetes (DM) (p=0,045), hipertensão (HAS) (p=0,032), dislipidemia (p=0,030) testes funcionais, resultado do teste (p=0,022), percentil escore de cálcio (p<0,001) e CACS (p<0,001). Nos pacientes sem DAC, houve associação com defeitos de perfusão e TCMD com cálcio que mostraram em casos de DM (30,0%) e CACS igual ou acima do percentil 75 (60,0%) e com valores acima de 400 (40,0%). O grupo com TCMD e perfusão normal apresentou maior percentual de ausência de HAS (78,6%). De outra forma, o grupo com perfusão normal e TCMD com cálcio mostrou mais pacientes com dislipidemia (42,5%) e distribuição dos percentis de CACS e CACS, semelhantes ao grupo com defeitos de perfusão e TCMD com cálcio. No grupo dos pacientes com DAC conhecida, também houve associação entre CACS e a extensão da aterosclerose coronária. Não houve associações entre os resultados da cintilografia e TCMD e outras variáveis. No subgrupo de 128 pacientes, em que se conseguiu seguimento tardio (média de 824,5 dias; DP de 385,9), aconteceram dois óbitos (1,6%), nenhum de causa cardiovascular. O evento mais frequente foi cinecoronariografia (CAT) (21,1%), seguida da angioplastia (ATC) (9,4%) e revascularizações cirúrgicas (3,1%). Não houve infarto do miocárdio (IM). De forma similar, não foram observados determinantes significativos da evolução tardia desses pacientes. Conclusões: Embora o CAC tenha sido tão frequente, como perfusão normal no SPECT, menos da metade daqueles com SPECT normal podem apresentar cálcio coronário à TCMD. Esta combinação de resultados (SPECT normal e cálcio) tinha associação com dislipidemia. Além disso, DM, CACS > 400 e percentil igual ou superior a 75% foram associados com SPECT anormal e cálcio na MDCT. A MDTC combinada ao SPECT foi capaz de detectar isquemia em pacientes com estenose coronariana conhecida, mas não havia associações entre o grau de estenose ou a presença, ou ausência de isquemia e sua extensão, com os resultados combinados. Houve uma baixa taxa de eventos no subgrupo de acompanhamento. / Background: The calcium in coronary arteries identifies the presence of coronary atherosclerosis, even in early stages. On the other hand, the decision about the best form of treatment this entity is based on the use of functional tests, in particular the myocardial perfusion scintigraphy (SPECT). There are doubts about the correlation between the results of these two exams, what could be, at least in part explained by the fact of these tests assess distinct phases of this entity. This study aims to evaluate the use of a combined functional and anatomical approach through SPECT and coronary computed tomography with multi-detectors (MDCT) in determining the calcium score (CACS),presence of stenosis or ischemia and examine the combined results with other demographic, clinical and functional variables, in a Brazilian population with suspected or known coronary artery disease (CAD). Methods: we retrospectively analyzed 413 patients who underwent to SPECT and MDCT by their physician indications during the year 2009, with less than 90 days interval between the two studies. CACS was automatically defined by dedicated software and the Agatston score was semi-automatically calculated. SPECT and MDCT results were evaluated by semi-objective visual quantification. The correlations of both tests results were analyzed and follow-up data were obtained through contact with assistant physician or analysis of hospital records. Results: We included 303 patients with suspect or known DAC who underwent to both, SPECT and MDCT (75.9 % men, mean age 55.8 ± 10.6 years; range:32-86 years); it was observed that 73,3% had normal perfusion studies, CAC was present 71,6% patients and 48.2% had normal perfusion and MDCT with calcium. In 177 patients without DAC there were association between MDCT and SPECT results and following variables: diabetes (DM) (p=0.045), hypertension (HAS) (p=0.032), dyslipidemia (p=0.030), functional test results (p=0.022), percentile of calcium score (p<0.001) and CACS (p<0.001). Patients without DAC, with perfusion defects and calcium showed more occurrences of DM (30.0%) and CACS equal to or above the 75 percentile (60.0%) and with values above 400 (40.0%). The group with normal MDCT and perfusion had higher percentage of absence of HAS (78.6%). The group with normal perfusion and MDCT with calcium had the highest percentage of patients with dyslipidemia (42.5%) and distribution of the calcium score percentiles and CACS were similar to the group with perfusion defects and MDCT with calcium. In the group with known CAD there was association between DM, extent of coronary disease and CACS. There were no associations between the results of SPECT and MDCT and other variables. In the subgroup of 128 patients with follow-up, the average time was 824.5 days (SD 385.9), there were 2 deaths (1.6%) confirmed, however none of cardiovascular cause. Coronary angiography (CATH) (21.1%) was the most frequent event, followed by percutaneous angioplasty (PTCA) (9.4%). Surgical revascularizations were much less frequent (3.1%). There was no myocardial infarction (MI). Similarly, there were no markers of long term prognosis in this sample. Conclusions: Although CAC was as frequent as normal perfusion in SPECT, less than half with normal SPECT may have calcium on MDCT. This results combination (normal SPECT and calcium) had association with dyslipidemia. Also, DM, CACS >400 and percentile equal or above 75% were associate with abnormal SPECT and calcium on MDCT. MDCT combined to SPECT was able to detect ischemia in patients with known coronary stenosis, but there were no associations between the degree of stenosis, or the presence or absence of ischemia and its extent with the combined results. There was a low event rate in the follow-up subgroup.

O fenômeno do precondicionamento isquêmico é definido como o aumento da tolerância à isquemia e à lesão de reperfusão, induzida por curtos e sucessivos episódios de isquemia prévios a período de isquemia prolongada. A angina do aquecimento e a de pré-infarto são duas condições clínicas relacionadas ao precondicionamento. Este fenômeno apresenta duas fases distintas, clássica ou precoce e tardia. A atenuação do infradesnível do segmento ST provocada pelo precondicionamento precoce está bem documentada, porém sua expressão cintilográfica permanece controversa. O objetivo desta pesquisa foi avaliar se as atenuações eletrocardiográficas do precondicionamento durante testes sequenciais estão associadas a modificações simultâneas das imagens de cintilografia de perfusão miocárdica em indivíduos com doença coronariana. Vinte e três pacientes foram selecionados entre março de 2009 e julho de 2011. A média de idade foi 64,5 anos (dp=7,0), 19 (82,6%) do sexo masculino e todos tinham lesão coronária em pelo menos um vaso superior a 60%. A medicação antiisquêmica foi suspensa por três a cinco dias. Os pacientes foram submetidos a três testes ergométricos a partir do exame de seleção, sendo dois deles sequenciais e o terceiro realizado após sete dias. A injeção do radiofármaco sestamibi-Tc-99m no teste de precondicionamento e contraprova foi administrado no tempo de aparecimento do infradesnível de ST de -2,0 mm na derivação MC5 e/ou dor precordial anotados no teste inicial ou de seleção. A imagem cintilográfica foi adquirida entre 60 a 90 minutos após o esforço. Os resultados do segundo teste (precondicionamento) mostraram aumento significativo do tempo para o aparecimento da depressão do segmento ST de 1,0 mm (338±130) e 2,0 mm (431±126), em relação ao teste inicial (245±96; 366±103) p<0,001. A diferença na redução do valor máximo de infradesnível de ST entre os três testes foi significativa (3,8±0,8; 2,3±0,6; 3,1±1,0) p<0,001. Houve redução significativa nos escores de perfusão de estresse (p=0,045) entre o primeiro e o segundo testes, bem como para o escore da diferença entre o estresse e repouso (p= 0,03), sem diferença na extensão da área de isquemia entre as três etapas detectadas pela cintilografia (p=0,691). Em conclusão, houve redução significativa das alterações eletrocardiográficas induzidas pelo precondicionamento isquêmico precoce em maior proporção do que as observadas nas respectivas imagens de cintilografia de perfusão miocárdica; não se observou associação entre a redução da depressão do ST e a redução do escore de perfusão na fase de precondicionamento, nem correlação entre a magnitude do infradesnível máximo de ST e a redução do escore de perfusão (r=0,07 e p=0,75). / The phenomenon of ischemic preconditioning is defined as the increase of tolerance to ischemia and injury of reperfusion induced by short and consecutive episodes of isquemia prior to prolonged arterial occlusion. Warm-up and pre-infarction angina are two clinical conditions regarding this phenomenon. The ischemic preconditioning has two distinct windows designed as classical and late. The improvement of ST depression induced by classical preconditioning is well documented, however its scintigraphy expression is still controversial. The aim of this research was to assess whether the reduction of ST depression induced by preconditioning during these sequencial exercise testing are associated to simultaneous alterations of the scintigraphy images of myocardial perfusion in individuals with coronary artery disease. From March 2009 to July 2011, 23 patients were selected, mean age 64,5 (sd=7,0), 19(82,6%) male. All patients had coronary artery stenosis at least 60% in one vessel. The anti ischemic therapy was discontinued for three days. Patients underwent three exercises testing after screening process; two of these tests were in a sequence and the other one performed after seven days. Tc-99m-sestamibi radiotracer injection was applied in the preconditioning test as well as for the third test at the time of development of ST depression 2,0 mm in the CM5 lead and/or chest pain estabilished in the screening process or first test. The scintigraphy image was obtained from 60 to 90 minutes after exertion. The results of the preconditioning test showed a significant increase of time for manifestation of the ST depression 1,0 mm (338±130) and 2,0 mm (431±126) regarding the first test (245±96; 366±103), p<0,001. There was a significant difference in the decrease of maximum value of ST depression among the three tests (3,8±0,8; 2,3±0,6; 3,1±1,0), p<0,001. A significant reduction in stress perfusion score (p=0,045) occurred between the first and second test as well as for the difference score between stress and rest (p=0,03). However, there was not a significant difference in the total defect size among the three stages detected by myocardial scintigraphy (p=0,691). In conclusion, there was a significant decrease of electrocardiographic alterations resulting from early preconditioning in greater proportion than the observed in scintigraphy images. It was not observed an association between the decrease of ST depression with the stress perfusion score during the preconditioning period nor the correlation between the magnitude of the maximum value of ST depression and the decrease of perfusion score (r=0,07 and p=0,75).

La dystrophie musculaire de Duchenne de Boulogne (DMD) est une myopathie héréditaire liée au chromosome X et causée par une mutation du gène de la dystrophine. Affectant un garçon sur 5000, cette maladie entraine une dégénérescence progressive des muscles striés squelettiques et cardiaques. A ce jour, la DMD demeure une maladie invalidante, incurable et les personnes atteintes ont une espérance de vie de 30 ans. Parmi les thérapies innovantes en cours de développement, la thérapie cellulaire est une stratégie prometteuse. Cependant elle présente plusieurs limitations notamment liées à l’efficacité des types cellulaires utilisés et le devenir des cellules après injection in vivo. Le premier objectif de cette thèse est le développement d’une méthode d’imagerie pour étudier à l’échelle de l’organisme et de façon non invasive la biodistribution et la survie des cellules suite à leur injection systémique dans un modèle préclinique pertinent, le chien GRMD (Golden Retriever Muscular Dystrophy), un modèle animal reproduisant fidèlement le phénotype DMD. Notre attention s’est portée sur l’utilisation du symporteur sodium iode (NIS) pour le suivi non invasif des cellules. Nous avons obtenu des cellules myogéniques exprimant le NIS, autorisant leur visualisation par scintigraphie grâce à la propriété d’absorption du technétium 99m conférée par ce symporteur. Nous avons montré in vitro que le NIS est fonctionnel pour la capture de radioactivité même après une différentiation avancée des cellules. En parallèle, nous nous sommes intéressés au type cellulaire. Les cellules primaires ayant une capacité de renouvellement limitée, cela restreint leur utilisation en thérapie et leur modification génomique. Afin de contourner cette limitation, plusieurs protocoles visant à obtenir des cellules souches pluripotentes induites (iPSCs) dérivées de cellules canines ont été utilisés. De plus, pour ne plus être dépendant de l’immunosuppression imposée par les greffes allogéniques, nous avons utilisé le système d’édition génomique CRISPR/Cas9 pour mettre au point une correction des cellules GRMD afin de permettre la réalisation de greffes autologues. Nous avons également utilisé le système CRISPR/Cas9 pour réaliser l’insertion ciblée du gène NIS dans un site précis du génome des cellules. Les résultats obtenus autorisent le développement de programmes comparant le potentiel thérapeutique de cellules dans un modèle préclinique de la DMD. / Duchenne muscular dystrophy (DMD), an X-linked recessive myopathy, is caused by mutations in the dystrophin gene. One boy out of 5000 is affected by this disease, which induces a progressive loss of skeletal striated and cardiac muscles. To date, DMD remains an invalidating disease and there is no cure for it. People suffering from DMD usually die in their 30’s. Among the innovative therapies currently under development, cell therapy is a promising strategy. However, it has some limitations related notably to a low efficiency of tested therapeutic cells and their tracking in vivo after injection. The first aim of this thesis is to develop an imaging method allowing non-invasive monitoring of biodistribution and survival of cells at the scale of a large organism, following systemic injection in the GRMD dog (Golden retriever muscular Dystrophy, a relevant animal model of DMD, as it replicates finely the DMD phenotype). We took interest in the sodium iodide symporter (NIS) as an imaging reporter. We induced the expression of the NIS in myogenic cells to allow visualization of the cells by scintigraphy thanks to its ability to uptake technetium 99m. We showed that NIS is functional in the cells and they maintain their ability to differentiate. Primary cells have a limited self-renewal capability restraining their use in human cell therapy and gene editing. To overcome this limitation, we used several protocols to derive induced pluripotent stem cells (iPSCs) from adult canine cells. Furthermore, to avoid immune suppression protocols, we used the CRISPR/Cas9 gene editing tools to design a correction strategy of the GRMD mutation for future autologous injections. We also used CRISPR/Cas9 to perform a targeted integration of the NIS gene in a safe harbor locus. Results allow us to develop protocols to compare the therapeutic potential of candidate cells in a preclinical model of DMD.

Bakgrund: Skelettscintigrafi är en nuklearmedicinsk undersökning. Undersökningen är den mest använda nukleardiagnostiska metoden och den genomförs ofta som en helkroppsundersökning. För att undersökningen ska kunna erhålla sin diagnostiska kvalitet, samt följa strålsäkerhetsmyndighetens rekommendationer behövs det mer kännedom till hur optimeringen ska följa as low as reasonably achievable (ALARA). Studiens syfte var att optimera patientstråldos samt att undersöka hur injicerad aktivitet kan anpassas efter patientens specifika parametrar. Metod: Studiegruppen bestod av 85 patienter som genomgick skelettscintigrafier vid Central sjukhuset i Karlstad, från perioden februari-april 2020. Resultat: Visade att både ålder och vikt är patientspecifika variabler som borde tas till betraktning vid bestämning av injicerad strålningsdos. Konklusionen: För att optimera undersökningen för varje patient bör injicerad aktivitet anpassas efter både kroppsvikt och ålder. Fler studier där andra parametrar undersöks måste genomföras. / Background: Bone scintigraphy is a nuclear medicine procedure. It is the most used nuclear diagnostic method and provides the opportunity to perform a full-body examination. For the method to retain its diagnostic quality, and to follow the recommendations of the Radiation Safety Authority, more knowledge is required on how the optimization should follow as low as reasonably achievable (ALARA). The purpose of the study was to optimize patient radiation dose and to investigate how the injected activity can be adapted to patient-specific parameters. Method: The study group consisted of 85 patients who underwent bone scintigraphy at the Central Hospital in Karlstad, from the period February-April 2020. Result: Showed that age and weight are patient-specific variables that should be considered when determining injected radiation dose. Conclusion: To optimize the examination for each patient, injected activity should be adjusted according to the patient’s body weight and age. More studies in where other parameters are investigated must be carried out.

Arbetsutlöst myokardischemi kan diagnostiseras med arbetsprovet, främst genom parametern ST60-sänkning under arbete samt återhämtningsfasen. Tidigare studier har visat arbetsprovets låga diagnostiska förmåga av arbetsutlöst myokardischemi och klassificerat det som en osäker metod, speciellt för kvinnor, och få studier har gjorts på kvinnor för förbättring. En justering av ST60-sänkning med hänsyn till hjärtfrekvensen (HR) har gjorts i flera studier, i försök att utveckla diagnostiken. När hjärtfrekvensen ritas grafiskt mot ST60- sänkning erhålls en ST/HR loop bestående av arbetsfasen och återhämtningsfasen. Den normaliserade arean (NA), som erhålls från ST/HR- loopen, är ett mått på sannolikheten för ischemi och dess grad. Studiens syfte är att, utifrån ST/HR loopars NA-värden från arbetselektrokardiogram, avgöra om diagnostiken av ischemi hos kvinnor kan förbättras i jämförelse med den konventionella bedömningen som baseras på ST60-sänkningen i slutet av arbete. Myokardscintigrafi (facitmetoden) och arbetsprov har utförts på den klinisk fysiologiska avdelningen i lund. Kontrollgruppen bestod av 80 kvinnor med normal myokardscintigrafi medan gruppen ”sjuka” omfattar 26 patienter som med myokardscintigrafi bedömts ha arbetsutlöst myokardischemi. För att i denna studie påvisa om det föreligger en statistisk skillnad mellan sjuka och friska, gällande NA – värdet respektive ST60-sänkningen, användes t-testet. En skillnad mellan sjuka och friska med NA- värde kunde inte påvisas och den konventionella bedömningen med ST60-sänkning visade sig inte heller vara bättre än NA-värdet för bedömning av arbetsutlöst myokardischemi.Nyckelord: arbets- EKG, myokardischemi, myokardscintigrafi, normaliserad area, ST60- sänkning, ST/HR- loop. / Exercise induced myocardial ischemia can be diagnosed with exercise–ECG, mainly through the parameter ST60-depression during the exercise and recovery phases. However, its low diagnostic accuracy, especially in women, has been proven. An adjustment of the ST60-depression with the heart rate has been done in several studies to develop the diagnosis. When the heart rate is plotted against the ST60-depression, an ST/HR- loop is obtained where both the exercise and recovery phases are included. The normalised area (NA) of the loop is believed to be significant for the diagnosis of ischemia. The aim of the study is to decide if the diagnosis of ischemia in women can be improved with the normalised area of the loop, from exercise– ECG, compared to the conventional assessment with ST60-depression at the end of exercise.Myocardial scintigraphy (the reference method) and exercise- ECG have been performed at the department of clinical physiology in Lund. The control group included 80 women with a normal myocardial scintigraphy while the other group consists of 26 patients who, according to their myocardial scintigraphy, have exercise induced myocardial ischemia. A distinction between the groups could not be made with the normalised area. The conventional assessment with ST60-depression was not better than the normalised area for the assessment of myocardial ischemia.Key words: Exercise- ECG, myocardial ischemia, myocardial scintigraphy, normalised area, ST60- depression, ST/HR-loop.

In dieser prospektiven, deskriptiven Querschnitts- und Pilotstudie sollten die Radioisotopen-Aufnahmemuster (radioisotope uptake - RU) der Reservekrone und des parodontalen Knochens der Ober- und Unterkieferbackenzähne (CT) bei klinisch gesunden Pferden beschrieben und die Auswirkungen des Alters auf die RU bewertet werden.:Table of Contents Abbreviations: .......................................................................................................... VI 1. Introduction ........................................................................................................ 1 2. Literature overview ............................................................................................ 3 2.1. Evolution of equine dentistry ......................................................................... 3 2.2. Epidemiology of equine dental pathology ..................................................... 5 2.3. Diagnostic imaging modality and equine dental disorders ............................ 5 2.4. Bone scintigraphy as diagnostic tool of equine dental disorders .................. 6 2.5. Literature review of equine dental scintigraphy ............................................ 8 3. Publication ........................................................................................................ 10 Scintigraphic evaluation of the cheek teeth in clinically sound horses ............ 10 3.1. Author contributions .................................................................................... 11 3.2. Abstract ....................................................................................................... 12 3.3. Introduction ................................................................................................. 12 3.4. Material and methods ................................................................................. 14 3.4.1. Subject selection ...................................................................................... 14 3.4.2. Scintigraphic examination ........................................................................ 14 3.4.3. Pilot study ................................................................................................ 15 3.4.4. Image processing and analysis ................................................................ 16 3.4.5. Statistical analysis .................................................................................... 16 3.5. Results ........................................................................................................ 17 3.6. Discussion .................................................................................................. 18 3.7. References ................................................................................................. 22 4. Discussion ........................................................................................................ 31 4.1. Animals ....................................................................................................... 31 4.2. Methodology ............................................................................................... 31 4.3. Results ........................................................................................................ 33 4.4. Study limitation ........................................................................................... 38 4.5. Clinical relevance ........................................................................................ 38 5. Zusammenfassung .......................................................................................... 40 6. Summary ........................................................................................................... 42 7. References ........................................................................................................ 44 8. Acknowledgements ......................................................................................... 51 / This prospective, cross-sectional, descriptive and pilot-designed study aimed to describe the radioisotope uptake (RU) patterns of the reserved crown and periodontal bone of the maxillary and mandibular cheek teeth (CT) in clinically sound horses and to evaluate the age effect on RU. For this purpose, 60 horses that underwent a bone scintigraphy for reason unrelated to head were included and divided equally into four age groups.:Table of Contents Abbreviations: .......................................................................................................... VI 1. Introduction ........................................................................................................ 1 2. Literature overview ............................................................................................ 3 2.1. Evolution of equine dentistry ......................................................................... 3 2.2. Epidemiology of equine dental pathology ..................................................... 5 2.3. Diagnostic imaging modality and equine dental disorders ............................ 5 2.4. Bone scintigraphy as diagnostic tool of equine dental disorders .................. 6 2.5. Literature review of equine dental scintigraphy ............................................ 8 3. Publication ........................................................................................................ 10 Scintigraphic evaluation of the cheek teeth in clinically sound horses ............ 10 3.1. Author contributions .................................................................................... 11 3.2. Abstract ....................................................................................................... 12 3.3. Introduction ................................................................................................. 12 3.4. Material and methods ................................................................................. 14 3.4.1. Subject selection ...................................................................................... 14 3.4.2. Scintigraphic examination ........................................................................ 14 3.4.3. Pilot study ................................................................................................ 15 3.4.4. Image processing and analysis ................................................................ 16 3.4.5. Statistical analysis .................................................................................... 16 3.5. Results ........................................................................................................ 17 3.6. Discussion .................................................................................................. 18 3.7. References ................................................................................................. 22 4. Discussion ........................................................................................................ 31 4.1. Animals ....................................................................................................... 31 4.2. Methodology ............................................................................................... 31 4.3. Results ........................................................................................................ 33 4.4. Study limitation ........................................................................................... 38 4.5. Clinical relevance ........................................................................................ 38 5. Zusammenfassung .......................................................................................... 40 6. Summary ........................................................................................................... 42 7. References ........................................................................................................ 44 8. Acknowledgements ......................................................................................... 51

Neuroendocrine tumours generally show an overexpression of somatostatin receptors on their cell membranes, mainly subtype 2. This is taken advantage of in diagnosis and therapy by using synthetic somatostatin analogues that can be labelled with radionuclides to visualize and treat tumours with an overexpression of somatostatin receptors. The method traditionally used for visualization is somatostatin receptor scintigraphy (SRS) with 111In-DTPA-octreotide but this method is gradually being substituted by 68Ga-DOTATOC PET/CT. To evaluate patients for peptide receptor radionuclide therapy, it is mandatory for the patient to be examined by both methods. In the evaluation, the tumours are graded according to the Krenning scale on the images from the SRS. Patients with sufficient tumour uptake of somatostatin analogues are eligible for peptide receptor radionuclide therapy (PRRT). The aim of this study was to compare the tumour’s Krenning scores from SRS to the Krenning scores, quantitative indices and TNR-values from the 68Ga-DOTATOC PET/CT images. This was done to investigate if the Krenning scale could be applied to PET/CT enabling the patient to undergo only PET/CT for diagnosis and evaluation prior to PRRT. This study, including 28 patients, found no strong correlation between the Krenning scores from the SRS and the scores from 68Ga-DOTATOC PET/CT. However, a better correlation was shown between the Krenning scores from SRS and TNR-values where the quantitative indices SUVmax and SUVmean were divided with the SUVmean of the spleen. These findings could be worth exploring further in future studies, incorporating larger number of patients.

A crescente incidência da aterosclerose na população adulta e a obstrução da artéria renal são condições relacionadas à hipertensão renovascular. Independente das comorbidades presentes, a estenose de artéria renal é, por si só, importante causa de mortalidade cardiovascular. Frente a tal realidade, determinar o exame ou exames que possam identificar precocemente esta condição mórbida pode mudar a história natural da doença renovascular. Objetivo: Definir sensibilidade, especificidade, valor preditivo positivo e valor preditivo negativo dos exames não invasivos na estenose da artéria renal. Associar estes achados com a análise vascular quantitativa (QVA) das artérias renais. Métodos: Estudo prospectivo com 61 pacientes recrutados entre janeiro de 2008 e agosto de 2011. As características populacionais, os exames de ultrassom Doppler, cintilografia renal com DTPA e a tomografia computadorizada foram selecionados e seus resultados comparados à arteriografia digital das artérias renais e ao QVA. Resultados: A média das idades foi de 65,43 (DP 8,7) anos. Das variáveis relacionadas à população do estudo e comparadas à arteriografia, duas identificaram relação com a estenose da artéria renal, a disfunção renal e os triglicerídeos. A mediana do ritmo de filtração glomerular de 52,8 ml/min/m2 identificou uma razão de chance para estenose de artéria renal de até 10 vezes. Os triglicerídeos associaram-se a uma menor presença de estenose na artéria renal, p < 0,037. A análise da sensibilidade, especificidade, valor preditivo positivo e negativo dos diferentes testes diagnósticos permitiu identificar aquele que melhor detectava a estenose nos suspeitos e afastava nos sadios. O ultrassom doppler com sensibilidade de 82,90%, especificidade 70,00%, valor preditivo positivo 85,00% e preditivo negativo 66,70% e a angiotomografia com sensibilidade de 68,30%, especificidade 80,00%, valor preditivo positivo 87,50% preditivo negativo de 55,20%, foram os exames que permitiram predizer as maiores chances de estenose da artéria renal nos portadores e afastar na população sem estenose. A associação das características populacionais com o QVA, permitiu identificar duas novas variáveis, o sexo e a idade. A média do grau de estenose, 33,47% (DP 29,55) quantificada pelo QVA, identificou menores graus de estenose que na análise visual dos angiogramas. Exames não invasivos positivos em estenoses menores do que 60% da luz do vaso também foram identificados . Os resultados identificados pela curva ROC demonstraram respectivamente a arteriografia, a angiotomografia e o ultrassom Doppler como os exames com melhores chances em predizer estenose significativa da artéria renal. Conclusão: A angiotomografia e o ultrassom Doppler trouxeram qualidade e alta possibilidade no diagnóstico da estenose da artéria renal, com vantagem para o segundo, pois não há necessidade do uso de meio de contraste na avaliação de uma doença que, frequentemente, está acompanhada por portadores de disfunção renal, disfunção ventricular esquerda grave e diabetes melito. A incorporação de uma forma objetiva de medidas das artérias renais aprimora os resultados da angiografia invasiva. / The increasing incidence of atherosclerosis in adults and renal artery stenosis are conditions related to renovascular hypertension. Regardless all risk factors, renovascular stenosis is by itself an important cause of cardiovascular mortality. Choosing appropriate tests that can early identify this morbid condition can change the natural history of renovascular disease. Objective: To define sensitivity, specificity, positive and negative predictive value of non- invasive tests in renal artery stenosis. Associate these findings with the renal arteries quantitative vascular analysis (QVA). Methods: Prospective study with 61 patients selected between January 2008 and August 2011. The population characteristics, Doppler ultrasound scanning, DTPA renal scintigraphy and computed tomography were selected and their results compared with renal arteries digital angiography as well as the comparison to QVA. Results: The mean age was 65.43 (SD 8.7). The risk factors of the study population compared to angiography identified two variables: renal dysfunction and triglycerides. The median glomerular filtration rate of 52.8 ml/min/m2 identified an odds ratio for renal artery stenosis up to 10 times. Triglycerides were associated with lower presence of renal artery stenosis p < 0.037. The analysis of sensitivity, specificity, positive and negative predictive values of different diagnostic tests allowed the identification of the stenosis in the group of suspected patients and this possibility was discarded in the group of healthy patients. Doppler ultrasound scanning with 82.90% sensitivity, 70.00% specificity, 85.00% positive predictive value, 66.70% negative predictive value and computed tomography with 68.30% sensitivity, 80.00% specificity, 87.50% positive predictive value and 55.20% negative predictive value. These were the tests which supplied better chances to predict renal artery stenosis in patients with or without stenosis. The relationship of population characteristics with QVA identified two new variables, gender and age. The mean degree of stenosis 33.47% (SD 29.55) quantified by QVA identified lesser degrees of stenosis than in visual analysis of angiograms. Non- invasive positive stenoses less than 60% of vessel lumen were identified. The results identified by the ROC curve showed respectively angiography, computed tomography, and Doppler ultrasound scanning as better chances for predicting renal artery stenosis. Conclusion: Computed tomography, Doppler ultrasound scanning have brought high quality and ability in the diagnosis of renal artery stenosis, with an advantage to Doppler, which avoids the use of contrast medium in the evaluation of a disease that is often accompanied by patients with renal dysfunction, severe left ventricular dysfunction and diabetes mellitus. The introduction of new methodology to measure renal arteries will certainly improve the angiography results.