Der TAIGA Detektor (“Tunka Advanced Instrument for cosmic ray physics and Gamma Astronomy”) testet eine neue Nachweismethode der erdgebundenen Cherenkov Gamma Astronomie fuer 10TeV bis einige PeV, und fuer kosmische Strahlung oberhalb 100TeV: die Kombination abbildender und nicht-abbildender Cherenkov Detektoren in einem hybriden System. Im Fokus der Arbeit steht TAIGA-HiSCORE - ein Cherenkov Detektorfeld mit grosser Apertur zur Messung der Zeitstruktur der Cherenkovlichtfront in atmosphaerischen Luftschauern (EAS). Die Praezisonsvermessung der Schauerrichtung basiert auf (1) sub-nsec Zeitsynchronisation aller Detektoren, und (2) einer neuentwickelten Zeitkalibrationsmethode. Die Genauigkeit wird bestimmt mit experimentellen und simulierten EAS-Daten, spezieller LED-Kalibration und dem LIDAR Laserstrahl aus der International Space Station (ISS). Mit den HiSCORE9 Daten (2013-2014) wird die sub-nsec Zeitsynchronisation durch das White Rabbit Zeitsystem unter realen Bedingungen nachgewiesen. Eine neue, auch fuer grosse Cherenkov-Detektorfelder praktikable Zeitoffset-Kalibration aller Detektoren wurde entwickelt, und fuer HiSCORE28 (2015-2018) angewandt. Diese hybride Kalibration basiert auf EAS-Ereignissen und direkter LED-Kalibration fuer lediglich eine begrenzte Zahl von Detektoren. Die Genauigkeit der Luftschauer-Richtungsrekonstruktion wird ueber die “Schachbrett-Methode” MC-unabhaengig bestimmt zu 0.4° an der Energieschwelle (50TeV) und <= 0.2° fuer > 100TeV. Eine wichtige Zufallsentdeckung war mit HiSCORE28 moeglich: der Laser des ISS-CATS-Lidars wurde in richtungsrekonstruierten Daten von HiSCORE28 nachgewiesen. Mit den “ISS Ereignissen” gelang es, sowohl die Rekonstruktionsgenauigkeit von HiSCORE, als auch das “absolute pointing” zu messen (<=0.1°) - besonders wichtig, da eine starke Gamma-Quelle im Datensatz bisher nicht nachgewiesen wurde. Im Schlussteil der Arbeit wird ein Methode zur Punktquellensuche im gesamten Gesichtsfeld von TAIGA-HiSCORE vorgestellt. / The TAIGA (Tunka Advanced Instrument for cosmic ray physics and Gamma Astronomy) detector is a new ground-based Cherenkov detection technology for gamma-astronomy from 10TeV up to several PeV, and cosmic rays (CR) above 100TeV. The main topic of this work is TAIGA-HiSCORE, the wide-aperture air Cherenkov timing array. The focus is on precision extensive air shower (EAS) arrival direction reconstruction, achieved by (1) sub-nsec time-synchronization between the array stations, and (2) a newly developed array time calibration procedure. The performance is verified using simulated and experimental data from EAS, dedicated LED calibration, and a LIDAR laser beam from the International Space Station (ISS). The analysis of the HiSCORE 9 data (2013-14), collected with a data acquisition system (DAQ) based on the White Rabbit (WR) timing system, allows to verify the sub-nsec time synchronization between the array stations. The analysis of HiSCORE 28 data (2015-2018) addresses the problem of achieving an easy-to-perform time calibration for large area ground-based Cherenkov array. A new "hybrid" calibration method is developed, which makes use of EAS data, and requires direct LED calibration of only a few array stations. The "chessboard" method is applied on the reconstructed data to obtain a MC-independent estimation of the detector angular resolution, found to be 0.4° at threshold (~50TeV) and <= 0.2° above 100TeV. A serendipitous discovery was made in this work: a signal from the CATS-LIDAR on-board the ISS was found in the HiSCORE 28 data. These "ISS-events" are used to verify the detector performance, in particular the absolute angular pointing (<= 0.1°), particularly important since a strong gamma point source has not yet been detected by the TAIGA-HiSCORE. The final part of the work presents a first preliminary approach to a wide aperture point source analysis, developed for the TAIGA-HiSCORE in stand-alone operation.

OBJETIVOS: A fotocoagulação retiniana transpupilar (FRP) tem seu uso, freqüentemente, limitado nos casos de opacidade acentuada dos meios oculares, situações nas quais pode-se empregá-la via transescleral. O presente estudo teve como objetivo realizar pesquisa experimental com o laser de diodo semicondutor infravermelho (LDI), a fim de estimar a reprodutibilidade, a segurança e a permeabilidade da parede ocular à sua atuação clínica (PPO), quando aplicado nesta técnica. MÉTODOS: Submeteram-se 18 olhos de 9 coelhos pigmentados, todos integrantes da raça Nova Zelândia (Oryctolagulos cuniculus), à fotocoagulação retiniana por LDI. No olho direito (OD) desses animais, realizou-se fotocoagulação via transescleral (FRT) sob parâmetros de potência e tempo pré-determinados clinicamente. No olho esquerdo (OE), foram repetidos os mesmos valores da potência e tempo usados no OD, mas, desta vez, sob uso da técnica da FRP. Passados 15 minutos das aplicações e após quatro semanas, estudos clínicos, baseados na retinografia, e histopatológicos foram realizados. RESULTADOS: Existe uma constante de PPO durante aplicação da FRT, cuja taxa varia de 58,95 a 63,87%. Observou-se que a média da PPO sob 300 mW (63,14%) é significativamente superior àquela encontrada sob 500 mW (59,11%), com significância de 5%. CONCLUSÕES: Este estudo sugere a existência da relação dose-resposta em relação aos parâmetros empregados na FRT, com PPO mensurável e boa reprodutibilidade clínica. Nenhuma rotura, hemorragia ou descolamento da retina (DR) foi constatado aos exames subseqüentes às aplicações do LDI, o que torna o uso do método viável e seguro no modelo experimental / PURPOSE: Recurrently retinal photocoagulation under poor visualization condition is often required. Transscleral delivery of infrared laser can be used as an alternative to standard transpupillary treatment. Based upon clinical aspects and retinographic measurements, we proposed to estimate reproducibility as well as ocular wall permeability rate for this treatment. Our primary goal was to evaluate whether this technique can deliver adequate photocoagulation at predetermined parameters. METHODS: In New Zealand pigmented rabbits, optimal transscleral infrared diode laser settings were administered to the right eye. With the same parameters, transpupillary photocoagulation was repeated to the left eye. Retinographic and clinical examinations were performed immediately and four weeks later. RESULTS: Ocular wall permeability rate varied between 58.95 and 63.87%. Average permeability using power of 300 mW (63.14%) was found to be higher than that encountered before its enhancement up to 500 mW (59.11%), (P < 0.05). CONCLUSIONS: Setting parameters showed dose-response effect. No retinal hole or retinal detachment was noticed in any rabbit. Transscleral infrared photocoagulation appeared to be a feasible, reproducible and secure method in the experimental model

O tratamento de pacientes com doenças inflamatórias oculares crônicas frequentemente implica no uso prolongado de drogas anti-inflamatórias sistêmicas como, corticosteroides e outros imunossupressores, podendo acarretar efeitos colaterais importantes. O uso local destas drogas pode contribuir para aumentar seus efeitos desejáveis e reduzir os efeitos colaterais. Implantes intraoculares biodegradáveis são capazes de disponibilizar o fármaco diretamente na cavidade vítrea em doses terapêuticas por período prolongado. O copolímero do ácido lático e glicólico (PLGA) é um clássico exemplo entre os polímeros sintéticos biodegradáveis aplicados em sistemas de liberação de fármacos devido à sua biocompatibilidade e ausência de toxicidade em testes in vivo. A ciclosporina A (CsA) é um imunossupressor largamente usado na clínica médica, e também tem sido empregada no tratamento de várias doenças inflamatórias intraoculares. O objetivo deste estudo foi avaliar a farmacocinética vítrea da CsA, quando aplicada por meio de implante biodegradável de PLGA intravítreo na concentração de 350 µg em olhos de coelhos, assim como avaliar a ocorrência de toxicidade retiniana causada pela presença intraocular do sistema de liberação de fármacos por meio de eletrorretinografia (ERG) e histopatologia. Dos sessenta coelhos que foram utilizados neste estudo, 38 receberam o implante intravítreo de PLGA contendo CsA e 22 somente os veículos. Somente o olho direito dos coelhos foi analisado na pesquisa. O estudo teve duração de oito semanas. Quatro coelhos do grupo CsA e dois do grupo controle foram sacrificados semanalmente para a coleta do vítreo e posterior estudo farmacocinético. Quatro animais de cada grupo foram escolhidos para terem a pressão intraocular aferida semanalmente. Seis coelhos foram submetidos a ERG no início e ao final do estudo, sendo então sacrificados, e os olhos processados para estudos histológicos da retina. O período inferido de permanência da CsA na cavidade vítrea foi de 17 semanas. Nos dois grupos, com e sem CsA, não foram observadas alterações histológicas na retina, entretanto houve importante redução da onda b nas fases escotópicas da ERG no grupo CsA, indicando toxicidade na via dos bastonetes após as oito semanas de seguimento. Em resumo, estes resultados mostraram que a CsA aplicada por meio de implantes oculares de PLGA na dose de 350 µg não causa alterações histológicas da retina, mas provoca um padrão exclusivo de diminuição da onda b. Em estudos futuros, seria interessante avaliar os efeitos de implantes contendo concentrações inferiores a 350 µg de CsA, e também, veículos que permitam que sua liberação seja mais lenta, evitando-se, assim, a toxicidade observada nos ERGs e confirmar sua aplicabilidade clínica como alternativa interessante para o tratamento de doenças oculares inflamatórias crônicas. / Treatment of patients with chronic inflammatory ocular diseases often involves the use of systemic anti-inflammatory drugs such as corticosteroids and other immunosuppressive agents for a long period of time, which may cause significant systemic side effects. Intraocular use of these drugs may help to improve their local beneficial effects and reduce systemic adverse effects. Biodegradable intraocular implants are able to deliver drugs directly into the vitreous cavity in therapeutic doses for an extended period of time. Poly-lactic-co-glycolic acid (PLGA) is a good example of synthetic biodegradable polymers used in ocular drug delivery systems due to its biocompatibility and absence of toxicity. Cyclosporine A (CsA) is a largely used immunossupressor, and it has also been employed for treatment of various intraocular inflammatory diseases. The objective of this work was to evaluate the pharmacokinetics of CsA, when applied in biodegradable PLGA intravitreal implants in rabbit eye and its retina toxicity by electroretinography and histopathology. Right eyes of sixty rabbits were used on this study, 38 received the PLGA implant containing 350 µg of CsA, and 22 the implant without the drug and were followed during 8 weeks. Four animals of CsA group and 2 of control group were sacrificed weekly to have their vitreous samples collected for subsequent pharmacokinetic study. Four animals from each group were chosen to have intraocular pressure measured weekly. Six animals of each group underwent electroretinography tests at baseline and at the end of the study. Then they were sacrificed and had their eyes processed for histological studies of the retina. It was hypothetically calculated that CsA would take 17 weeks to be completely delivery by this system. Histologically the retina did not show alterations in both groups, but there was a significant reduction in the b wave of the scotopic ERG phases in the CsA group indicating toxicity of the rods pathway after 8 weeks of follow-up. In summary, PLGA implants with 350 µg of CsA does not cause retinal histological changes, but decreases b wave amplitude. In future studies it would be interesting to test lower concentrations of CsA using this delivery system to decrease possible toxicity and to guarantee its clinical applicability.

Vários materiais têm sido injetados ou inseridos nas pregas vocais na tentativa de solucionar a incompetência ou insuficiência glótica. Contudo, poucos são os estudos que avaliam o processo cicatricial decorrente da enxertia destes materiais. O objetivo desta pesquisa foi quantificar e comparar as fibras colágenas no músculo vocal das laringes dos coelhos que foram submetidos a enxerto unilateral de gordura ou fáscia muscular com a prega vocal contra-lateral, que foi submetida ao mesmo procedimento, com exceção da enxertia. Estudamos 24 coelhos, divididos em dois grupos com 12 coelhos em cada um. No primeiro grupo, denominado F (Fáscia), os coelhos foram submetidos à inserção de enxerto de fáscia lata autóloga na prega vocal direita. No outro grupo, denominado G (Gordura), os coelhos foram submetidos a implante de gordura autóloga \"em bloco\" também na prega vocal direita. Todos os coelhos foram também submetidos ao mesmo procedimento na prega vocal esquerda, com exceção da colocação do enxerto. A prega vocal esquerda, desta forma, constituiu o \"controle\" para cada coelho. Metade dos coelhos, de cada um dos grupos (F e G), foi sacrificada após 90 dias do procedimento cirúrgico. A outra metade dos coelhos dos grupos G e F foi sacrificada após 180 dias do procedimento cirúrgico. As laringes foram removidas e as pregas vocais, direita e esquerda, foram preparadas histologicamente. Os cortes corados pelo método da picrosírius-polarização foram utilizados para a visualização e análise das fibras colágenas. O colágeno foi analisado morfometricamente através do método da Picrossírius-polarização com a utilização do software Image Pro Plus. Houve aumento do colágeno em todos grupos enxertados quando comparados com o grupo controle. A concentração do colágeno encontrada nos coelhos submetidos a enxerto de gordura foi significativamente maior quando comparados à concentração do colágeno nos coelhos submetidos a enxerto de fáscia muscular, tanto com 90 quanto com 180 dias. A enxertia de gordura e fáscia lata na prega vocal de coelho promoveu maior deposição de colágeno do que no grupo controle, sendo mais exuberante na inserção de gordura / Several materials have been injected or inserted in the vocal fold, in attempt to solve glottic insufficiency. Nevertheless, there is just a few papers that evaluates the inflammatory process resulted from these materials incorporation. The objective of this study was to quantify and compare the collagen fibers in the vocal muscle of the larynx from the rabbits in which unilateral fat and muscular fascia were introduced, to the contralateral vocal fold, in which the same procedure have taken place, except be the grafting. Twenty four rabbits were used in this study, divided into two groups, 12 rabbits each. In the first group, named F (from Fascia), the rabbits underwent the insertion of fascia lata into the right vocal fold. In the other group, named G (from Grease), the rabbits underwent implantation of autologous fat \"en bloc\" in the right vocal fold, as well. All rabbits have undergone the same procedure in the left vocal fold, except for the graft insertion. The left vocal fold, therefore, formed the control group for each rabbit. Half the rabbits, form each group (F and G), was sacrificed after 90 days, while the other half was sacrificed after 180 days from the surgical procedure. The larynxes were removed and the vocal folds, right and left, were prepared for histology, using the method of picrosirius-polarization for the coloration. The collagen fibers in the samples were analyzed using a computer software called Image Pro Plus. An increasing of the collagen was found in all the groups in which grafts have been placed, when compared to the control group. The collagen density found in those rabbits which underwent fat insertion was significantly higher than in those with muscular fascia insertion, for both periods of 90 and 180 days, as well. Fat and muscular fascia insertion in rabbits vocal fold resulted in a higher collagen deposition, when compared to the control group, being

Vários materiais têm sido injetados ou inseridos nas pregas vocais na tentativa de solucionar a incompetência ou insuficiência glótica. Contudo, poucos são os estudos que avaliam o processo cicatricial decorrente da enxertia destes materiais. O objetivo desta pesquisa foi quantificar e comparar as fibras colágenas no músculo vocal das laringes dos coelhos que foram submetidos a enxerto unilateral de gordura ou fáscia muscular com a prega vocal contra-lateral, que foi submetida ao mesmo procedimento, com exceção da enxertia. Estudamos 24 coelhos, divididos em dois grupos com 12 coelhos em cada um. No primeiro grupo, denominado F (Fáscia), os coelhos foram submetidos à inserção de enxerto de fáscia lata autóloga na prega vocal direita. No outro grupo, denominado G (Gordura), os coelhos foram submetidos a implante de gordura autóloga \"em bloco\" também na prega vocal direita. Todos os coelhos foram também submetidos ao mesmo procedimento na prega vocal esquerda, com exceção da colocação do enxerto. A prega vocal esquerda, desta forma, constituiu o \"controle\" para cada coelho. Metade dos coelhos, de cada um dos grupos (F e G), foi sacrificada após 90 dias do procedimento cirúrgico. A outra metade dos coelhos dos grupos G e F foi sacrificada após 180 dias do procedimento cirúrgico. As laringes foram removidas e as pregas vocais, direita e esquerda, foram preparadas histologicamente. Os cortes corados pelo método da picrosírius-polarização foram utilizados para a visualização e análise das fibras colágenas. O colágeno foi analisado morfometricamente através do método da Picrossírius-polarização com a utilização do software Image Pro Plus. Houve aumento do colágeno em todos grupos enxertados quando comparados com o grupo controle. A concentração do colágeno encontrada nos coelhos submetidos a enxerto de gordura foi significativamente maior quando comparados à concentração do colágeno nos coelhos submetidos a enxerto de fáscia muscular, tanto com 90 quanto com 180 dias. A enxertia de gordura e fáscia lata na prega vocal de coelho promoveu maior deposição de colágeno do que no grupo controle, sendo mais exuberante na inserção de gordura / Several materials have been injected or inserted in the vocal fold, in attempt to solve glottic insufficiency. Nevertheless, there is just a few papers that evaluates the inflammatory process resulted from these materials incorporation. The objective of this study was to quantify and compare the collagen fibers in the vocal muscle of the larynx from the rabbits in which unilateral fat and muscular fascia were introduced, to the contralateral vocal fold, in which the same procedure have taken place, except be the grafting. Twenty four rabbits were used in this study, divided into two groups, 12 rabbits each. In the first group, named F (from Fascia), the rabbits underwent the insertion of fascia lata into the right vocal fold. In the other group, named G (from Grease), the rabbits underwent implantation of autologous fat \"en bloc\" in the right vocal fold, as well. All rabbits have undergone the same procedure in the left vocal fold, except for the graft insertion. The left vocal fold, therefore, formed the control group for each rabbit. Half the rabbits, form each group (F and G), was sacrificed after 90 days, while the other half was sacrificed after 180 days from the surgical procedure. The larynxes were removed and the vocal folds, right and left, were prepared for histology, using the method of picrosirius-polarization for the coloration. The collagen fibers in the samples were analyzed using a computer software called Image Pro Plus. An increasing of the collagen was found in all the groups in which grafts have been placed, when compared to the control group. The collagen density found in those rabbits which underwent fat insertion was significantly higher than in those with muscular fascia insertion, for both periods of 90 and 180 days, as well. Fat and muscular fascia insertion in rabbits vocal fold resulted in a higher collagen deposition, when compared to the control group, being

Vários materiais têm sido introduzidos nas pregas vocais na tentativa de solucionar a incompetência glótica, porém poucos são os estudos que avaliam o processo cicatricial decorrente da enxertia destes materiais. O objetivo desta pesquisa foi quantificar o processo inflamatório celular na prega vocal de coelhos submetidos a enxerto unilateral de gordura ou fáscia muscular. Estudamos 24 coelhos, divididos em 2 grupos, nos quais gordura ou fáscia foi enxertada. O grupo controle foi formado pela prega vocal contralateral, a qual foi submetida ao mesmo procedimento, excetuando-se a colocação do enxerto. Metade dos coelhos de cada grupo foi sacrificada após 90 dias, enquanto a outra metade foi sacrificada após 180 dias da cirurgia. A densidade celular inflamatória peri-enxerto foi avaliada em todas as pregas vocais. Houve um aumento do infiltrado inflamatório no grupo submetido à enxertia de gordura, quando comparado ao submetido à enxertia de fáscia. Bem como ao grupo controle, após 90 dias. Quanto aos coelhos sacrificados após 180 dias, não houve diferença entre os grupos entre si e em relação ao grupo controle. Esse estudo sugere que o enxerto de fáscia parece ser mais aceitável que o enxerto de gordura para a prega vocal, uma vez que origina menor reação inflamatória tecidual / Several material have been introduced into the vocal folds in attempt to solve glottic incompetence, however just a few studies are related with the consequent inflammatory process. The aim of this article was to quantify the cellular inflammatory process in rabbit vocal fold, which have undergone unilateral fat or muscular fascia introduction. Twenty-four rabbits were allocated into two groups, in which muscular fascia or fat were implanted. The control group, formed by the contra-lateral vocal fold, underwent the same surgical procedure, except for the grafting. Half the rabbits from each group were sacrificed after 90 days from the surgery, while the other half was sacrificed after 180 days. The inflammatory cellular density around the graft was measured in all vocal folds. There was a higher cellular inflammatory reaction in the group submitted to fat grafting when compared to the group submitted to muscular fascia grafting, and to the control group, after 90 days. As for the rabbits sacrificed after 180 days, there was no significant difference between the implanted groups with each other, and with the control group. This study suggests that muscular fascia graft seems to be more acceptable than fat grafts for the vocal fold, as it produces a lower local inflammatory reaction

Le refroidissement in vivo du myocarde jusqu'à 32-34°C est une stratégie cardioprotectrice extrêmement puissante expérimentalement. La ventilation liquide totale (VLT) par des perfluorocarbones permet d'induire cette hypothermie très rapidement en utilisant le poumon comme bioéchangeur thermique, tout en maintenant des échanges gazeux normaux. L'objectif de notre travail de thèse a été d'étudier les effets de la VLT hypothermisante sur les lésions d'ischémie-reperfusion dans des modèles d'ischémie myocardique régionale et d'arrêt cardiorespiratoire chez le lapin. Dans une première étude, nous avons démontré que l'instauration per-ischémique d'un épisode de VLT hypothermisante permettait d'atteindre la température cible de 32-33°C en seulement 5 min chez des lapins chroniquement instrumentés soumis à 30 min d'occlusion coronaire. Cela permettait d'atténuer non seulement la taille d'infarctus mais également la dysfonction contractile post-infarctus. La taille d'infarctus était ainsi respectivement réduite de 89 et 71% lorsque la VLT était débutée à la 5ème ou à la 15ème min d'occlusion coronaire par rapport au groupe Témoin. Cette protection était associée à un effet bénéfique sur la fonction mitochondriale dont la capacité de rétention calcique était significativement accrue par l'hypothermie.Dans une seconde étude, nous avons montré que cet effet cardioprotecteur de la VLT hypothermisante n'était pas limité par un plateau de cardioprotection puisqu'il persistait lors d'ischémies prolongées (60 min) chez des lapins anesthésiés. Les tailles de l'infarctus et du no-reflow étaient en effet respectivement diminuées de 45 et 74% dans un groupe d'animaux soumis à une VLT hypothermisante à partir de la 5ème min d'occlusion coronaire par rapport au groupe Témoin. Lorsque la VLT était instaurée plus tardivement (20ème min d'occlusion coronaire), ces réductions restaient significatives (respectivement -30% et -60%) alors qu'un refroidissement conventionnel par application de couvertures froides n'induisait aucun bénéfice, même lorsqu'il était débuté dès la 5ème min d'occlusion coronaire.Grâce aux travaux précédents, nous avons obtenu la preuve de concept de l'effet cardioprotecteur de la VLT hypothermisante au cours d'une ischémie myocardique régionale. Cependant, la translation clinique de cette stratégie est probablement délicate dans la situation de l'infarctus du myocarde. Il nous a en revanche semblé qu'elle pourrait être également bénéfique au cours de la réanimation post-arrêt cardiaque. Pour étudier ce phénomène, nous avons mis au point un modèle expérimental d'arrêt cardiaque et de réanimation cardiopulmonaire chez des lapins soumis à un épisode de fibrillation ventriculaire. Nous avons ainsi montré que la VLT hypothermisante permettait d'augmenter significativement la survie et d'atténuer le syndrome post-arrêt cardiaque par rapport à une réanimation conventionnelle. Après 10 min d'arrêt cardiaque, la survie était par exemple respectivement de 7/10 vs 0/10 chez les animaux soumis à la VLT hypothermisante par rapport au groupe Témoin. Ces effets bénéfiques étaient directement liés à la rapidité d'induction de l'hypothermie par la VLT puisqu'une hypothermie conventionnelle par refroidissement externe et perfusion de fluides refroidis n'a pas permis d'induire de protection significative.En conclusion, la VLT hypothermisante est une approche puissamment protectrice lors d'ischémie myocardique régionale et au décours d'un arrêt cardiaque. L'évaluation plus approfondie de cette stratégie nécessite à présent le développement de dispositifs sécurisés pouvant être utilisés sur un modèle gros animal.MOTS-CLES : Ventilation liquide totale, perfluorocarbone, hypothermie, infarctus, no-reflow, arrêt cardiaque. LABORATOIRE D'ACCUEIL : Laboratoire de pharmacologie, INSERM U955 équipe 3, Ecole nationale vétérinaire d'Alfort, Faculté de médecine de Créteil, Université Paris-Est, Créteil. / Cooling the ischemic myocardium to 32-34 °C is known to be potently cardioprotective. Total liquid ventilation (TLV) with perfluorocarbons can induce such an hypothermia very fastly using the lung as a heat exchanger while maintaining normal gas exchanges. The aim of this thesis was to investigate its beneficial effects in experimental models of myocardial ischemia and cardiac arrest in rabbits.In our first study, we demonstrated that the institution of hypothermic TLV allowed achieving a cardiac temperature of 32-33°C within only 5 min in chronically instrumented rabbits subjected to 30 min of coronary artery occlusion. This was associated with a significant reduction in infarct size along with a dramatic attenuation of the post-ischemic myocardial contractile dysfunction. As example, infarct size was reduced by 89 and 71% when TLV was initiated at the 5th or 15th min of coronary artery occlusion, respectively. This protection was associated with an attenuation of the mitochondrial dysfunction, as shown by an increased calcium restrain capacity.In a second study, we demonstrated that the protective effect of hypothermic TLV was not limited by a ceiling of cardioprotection since infarct size reduction persisted following prolonged ischemia (60 min) in anesthetized rabbits. Infarct and no-reflow sizes were indeed reduced by 45 and 74% in animals subjected to hypothermic TLV from the 5th min of coronary occlusion as compared to corresponding Controls, respectively. In comparison, a conventional external cooling with cold blankets did not reduce infarct size even when instituted since the 5th of ischemia.Thanks to the previous works, we obtained the proof of concept that hypothermic TLV could offer a dramatic cardioprotection during regional myocardial ischemia. However, the clinical translation of this strategy might be challenging in the clinical scenario of ST-elevation myocardial infarction. This might conversely be less challenging and also beneficial to prevent the post-cardiac arrest syndrome in patients resuscitated from cardiac arrest. In order to investigate this phenomenon, we developed an experimental model of cardiac arrest and cardiopulmonary resuscitation in rabbits submitted to an episode of ventricular fibrillation. Accordingly, we have demonstrated in this model that hypothermic TLV significantly increased survival and attenuated the post-cardiac arrest syndrome as compared to conventional resuscitation. After 10 min of cardiac arrest, survival was for example 7/10 vs 0/10 in animals subjected to hypothermic TLV vs corresponding Controls, respectively. These beneficial effects were directly related to the rapidity at inducing hypothermia with TLV since conventional hypothermia using external cooling and infusion of cold fluids failed to induce a significant protection.In conclusion, hypothermic TLV can induce a dramatic protection during regional myocardial ischemia or following cardiac arrest and resuscitation. In order to further investigate this strategy, we are now requiring a secured device that can be used in large animals.KEYWORDS: total liquid ventilation, perfluorocarbon, hypothermia, infarct, no-reflow, cardiac arrest.Laboratory: Laboratory of Pharmacology, INSERM U955 équipe 3, Ecole nationale vétérinaire d'Alfort, Faculté de médecine de Créteil, Université Paris-Est, Créteil.

The experiments described in this thesis were designed to assess changes in pasture dynamics (biomass and species composition of pasture) of grazing land on the Southern Tablelands of ACT and NSW, after 16 combinations of rabbit control treatments had been applied. The rabbit control performed by CSIRO Division of Wildlife and Ecology consisted of all combinations of presence-absence of Poisoning (using sodium monofluoroacetate, 1080: POIS), Ripping (ripping warrens using a tractor fitted with ripping tynes: RIP), Fumigation (pressure fumigation using chloropicrin: FUM) and repeated follow-up fumigation (using phostoxin pellets one, six and eighteen months after completion of the initial treatment: ANN). The pasture was assessed before treatments were applied, and every six months after rabbit control treatments. Treatment combinations were assigned randomly in a 24 factorial design on a total of 32 sites. There was a significant increase of pasture biomass at the RIP+ANN treatment at post-treatment sample 5. The analysis of covariance did not detect any other significant increase or decrease of pasture biomass for any rabbit control treatment, at any posttreatment sample. A significant increase of grass species occurred for the treatments of POIS+RIP+FUM, POIS and RIP+ANN for the post-treatment samples of 1, 3 and 5 respectively. There was a significant increase of thistles at the rabbit control treatments of POIS+RIP+FUM+ANN (post-treatment sample 1), RIP, ANN, RIP+FUM, RIP+FUM+ANN and POIS+RIP+FUM+ANN (post-treatment sample 3) and RIP and FUM+ANN (post-treatment sample 5). A significant increase of weeds occurred at FUM (post-treatment sample 3) and at FUM+ANN (post-treatment sample 5). No significant changes in the amount of herbs or legumes was apparent for any rabbit control treatment or post-treatment sample. There were no significant decreases for any species group. Except for the significant results for post-treatment sample 1, all significant increases of biomass for any species group occurred during spring (post-treatment sample 3 and 5) which suggests a growth phase during spring then subsequent dieback (particularly for thistles and weeds), as any change was not detected in the following autumn sample. No strong trend is evident for any particular rabbit control treatments, or any combination of treatments. Analysis of covariance revealed that the rabbit control treatment of RIP+ANN showed significant increases in both total biomass of pasture and grass biomass during post-treatment sample 5. This treatment reduced the number of active entrances the most. Significant positive correlations were found between pasture biomass (total) with grass, herb, legume, thistle and weed species groups. Significant negative correlations between grass biomass and the number of active entrances were found when the rabbit control had been highly effective in reducing the number of active entrances. When rabbit control had not been very successful, there was a significant positive but low correlation with the number of active entrances. There was no significant relationship between the number of active entrances with the weight of rabbit dung pellets. It is reasoned that they are different measures of rabbit abundance. More rabbit dung pellets were found closer to the warren than further away from the warren, but there was no correlation between rabbit dung and pasture biomass. Rainfall was above average for most of the experiment, biomass increased accordingly, and rabbit control was highly successful. The resulting changes in the pasture were difficult to detect, although some increases in species composition groups occurred. It is reasoned that the changes observed are partly attributable to seasonal conditions, and to high rainfall. Grazing by domestic animals, sheep and cattle, had been found to be consistent throughout the experiment.

Listed as federally-endangered in 1990, the Lower Keys marsh rabbit (LKMR, Sylvilagus palustris hefneri) exists as a metapopulation in patches of wetland habitat in Florida’s Lower Keys. This study sought to address 2 priority actions identified by the LKMR Recovery Team: (1) monitoring of populations and (2) reintroduction. Monitoring the distribution and status of LKMR populations is critical for targeting future management actions. Informal transects for rabbit fecal pellets were used to survey habitat patches documented in1988–1995 surveys and to identify additional patches of occupied and potential habitat. Next, a buffer was created around patches to help managers account for uncertainty in rabbit movements and to identify groups of patches that might function as local populations. Surveys included 228 patches of occupied and potential habitat, 102 of which were occupied by rabbits. Patches were arranged in 56 occupied and 88 potential populations. Surveys revealed new patches of both occupied and potential habitat. Considering only areas included in 1988–1995 surveys, however, revealed a net decrease in the number of occupied patches. Many of the recently extirpated populations, which tended to occupy the periphery of larger islands or small neighboring islands, were unlikely to be recolonized without human intervention. Reintroduction provides a means of artificially recolonizing potential habitat. Two pilot reintroductions were conducted to evaluate this conservation strategy for the species. The second reintroduction was postponed, but the first effort met all criteria for short-term success, including survival comparable to a control group, fidelity to release sites, and evidence of reproduction. There are a limited number of potential source populations for translocations. Future efforts should consider using in-situ captive breeding to prevent potential long-term impacts to these populations. Few potential release sites exhibited suitable habitat quality and landscape context. Thus, for reintroduction to be more widely-applied for this species, it must be part of a comprehensive management plan involving land acquisition, control of secondary impacts from development, and habitat restoration and enhancement.

Per studiare le ripercussioni metaboliche e produttive di alterazioni della funzionalità del digerente sono state condotte tre sperimentazioni. Nella prima sono state controllate le condizioni di acidosi ruminale in bovine di allevamenti commerciali: in essi non si sono riscontrati valori di ph capaci di indurre seri effetti negativi a livello digestivo-metabolico, ma certamente a rischio. In tali condizioni, i più bassi valori di ph ruminali sarebbero soprattutto indice di una maggiore ingestione di alimenti, favorita anche da migliori condizioni generali di salute delle bovine. Nella seconda sperimentazione, l'applicazione di stress acuti a bovine in lattazione ha prodotto un rallentamento nel transito ruminale, soprattutto in animali in lattazione avanzata, confermando la possibilità che lo stress acuto rappresenti un fattore di rischio per anomalie digestivo/fermentative. Nella terza prova, relativa alla funzionalità del grosso intestino di conigli esposti a diete con diversi livelli di amido, performance produttive leggermente più favorevoli si sono registrate con la dieta più alta in fibra digeribile. A fronte di analoghe caratteristiche del digerente tra le tesi, alcuni parametri ematici ,soprattutto con riferimento allo status ossidativo, hanno permesso di porre in evidenza un quadro metabolico più favorevole associato all'uso di diete meno amidacee. Quindi, alterazioni dei processi fermentativi, possono avere conseguenze sul livello produttivo e sullo stato di salute dell'animale. Per una migliore interpretazione dei dati della funzionalità del digerente appare utile il supporto di taluni parametri ematici. / Three experiments were carried out to study the metabolic and productive effects of some changes of the digestive functionality. In the first experiment, the degree of ruminal acidosis was controlled on dairy cows from commercial farms: the low observed ph values were indices of risks but not so low to have serious adverse effects at digestive-metabolic level. However in these circumstances, the lower ph would be especially indices of a greater feed intake, in turn favoured by a better general animal health. In the second experiment, the application of acute stress to lactating cows showed digesta rumen passage rate of digesta, especially in late lactation, confirming the possibility that the acute stress could be a risk factor for digestive abnormalities. In the third one, on the large intestine functionality of rabbits exposed to diets with different levels of starch, some slightly better performances were obtained with the diet richer in digestible fibre. Though main digestive traits were unaffected by treatments, some blood parameters, particularly those linked to the oxidative status, revealed a more favourable metabolic situation associated with the use of less starchy diets. Hence, alteration of the fermentative processes may impair animal production and/or the animal health conditions. For a better interpretation of the parameters of the digestive system functionality the support of some specific blood parameters appears useful.