Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Orientador: Ione Morita / Banca: Margareth Aparecida Santini de Almeida / Banca: Maria Ines Rauter Mancuso / Resumo: Transformações sociais decorrentes do acelerado desenvolvimento urbano-industrial introduziram grandes mudanças no modo de vida. Considerando os adolescentes como tendo características próprias de um grupo em transição para a vida adulta, e as influências decorrentes do meio social e cultural, acrescenta-se mais um problema trazido pelo surgimento do HIV/Aids. Nessa condição específica de portador do HIV/Aids, tem-se que esse grupo redefine suas formas de enfrentar a vida, devido à exclusão social que a doença ainda provoca. Assim, o trabalho busca identificar a percepção de adolescentes portadores do HIV/Aids, atendidos no Ambulatório de Imunologia Especial do Hospital das Clínicas da Faculdade de Medicina de Botucatu/UNESP, sobre como é viver com a doença no ambiente familiar, na escola e no hospital. Conforme a OMS, os adolescentes situam-se entre 10 a 19 anos de idade. Selecionamos para entrevista semi-estruturada, treze adolescentes em tratamento durante o ano de 2011 e para os quais se apresentou o Termo de Consentimento Livre e Esclarecido aprovado pelo Comitê de Ética da Faculdade de Medicina. Dentre as concepções, questões como novos arranjos familiares, preconceito e estigma encontram-se presentes. Deste modo, dar voz aos jovens pacientes e reconhecer a reconfiguração de... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Considering the fact that adolescents typically show the characteristics of a group in transition to adulthood as well as the influences from their social and cultural milieus, another problem brought by the rise of HIV/AIDS is added. In this specific condition of carrying HIV/AIDS, this group of individuals redefines their forms of coping with life due to the social exclusion that such disease still causes. Hence this study aimed at identifying the perception of adolescents with HIV/AIDS attended to at the Special Immunology Outpatient Unit of the Botucatu School of Medicine University Hospital/UNESP of what it is like to live with the disease in their family environment, at school and in the hospital. According to WHO, adolescents are from 10 to 19 years old. It was used qualitative research with thirteen adolescents undergoing treatment in 2011, that was selected to participate in semi-structured interviews, to whom was presented a Free-Consent Form approved by the Ethics Committee of the School of Medicine. In this initial stage of presenting the first results, described the data found, classified according specific characteristics, such as the fact that all respondents studying in public schools. Because they are young, there is the need to expand educational projects on the topic. These policies should be proposed in order to meet and talk more openly with students and educators concerning health, disease and approach to patients. About the outpatient clinic, the patients ranged from feeling "normal", "good" and "great". These data lead to show that this space is the presence of humanization and that there is a good relationship between doctor and patient, considering that the multidisciplinary team seeks to meet the physical, mental and social these adolescents, indicating an adaptation of the traditional biomedical model... (Complete abstract click electronic access below) / Mestre

Yang Jie. / "January, 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 204-250). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Orientador: Lígia Maria Suppo Souza Rugolo / Banca: Lilian Dos Santos Rodrigues Sadeck / Banca: Maria Regina Bentlin / Resumo: As síndromes hipertensivas da gestação constituem importante causa de prematuridade. Os distúrbios respiratórios representam a principal morbidade de prematuros e a literatura é controversa quanto ao prognóstico respiratório de prematuros de mães hipertensas. Investigar a incidência de doenças respiratórias em prematuros e a associação entre as síndromes hipertensivas da gestação e a síndrome do desconforto respiratório (SDR). Estudo unicêntrico, observacional prospectivo e longitudinal, com prematuros nascidos na Maternidade do HC da FMB-UNESP entre maio de 2007 e outubro de 2008. Critérios de inclusão: ausência de diabete materno e malformação congênita. Excluídos os óbitos < 24 horas. Os prematuros foram estratificados em 2 grupos conforme a condição materna: hipertensa ou normotensa, e avaliados até a alta ou óbito. Variáveis maternas, gestacionais, de nascimento e neonatais foram analisadas por análise uni e multivariada tendo como desfecho de interesse a presença de doenças respiratórias. Foram estudados 421 prematuros, sendo 144 filhos de mães hipertensas e 277 de normotensas. A mediana da idade gestacional foi 34 semanas nos 2 grupos. A incidência de doenças respiratórias foi de 51%, sem diferença entre os grupos. SDR ocorreu em cerca de 30% e taquipnéia transitória do recém-nascido em 15% da amostra estudada. Na análise multivariada os fatores de risco para SDR foram: idade gestacional (OR= 0,5; IC95% 0,44 - 0,57); hipertensão materna (OR= 2,75; IC95% 1,41 - 5,34) e inibição do parto (OR= 2,57; IC95% 1,08 - 6,10). A morbidade respiratória foi elevada nos prematuros, mas não diferiu entre filhos de mães hipertensas e normotensas. As síndromes hipertensivas da gestação são fator de risco para SDR / Abstract: Hypertensive syndromes in pregnancy constitute an important cause of prematurity. Respiratory diseases are the major morbidities in preterm infants, and the literature is controversial with respect to the respiratory outcome of premature infants born to hypertensive mothers. To investigate the incidence of respiratory diseases in preterm infants and the association between hypertensive syndromes in pregnancy and the respiratory distress syndrome (RDS). Single-center, observational, prospective, longitudinal study on preterm infants born at the Maternity Ward of FMB-UNESP University Hospital, from May 2007 to October 2008. Inclusion criteria: absence of maternal diabetes and congenital malformation. Deaths < 24 hours were excluded. The preterm infants were stratified into 2 groups according to maternal conditions: hypertensive or normotensive, and evaluated until hospital discharge or death. Maternal, gestational, birth and neonatal variables were analyzed by uni and multivariate analysis, and the presence of respiratory diseases was the outcome of interest. Four hundred and twenty-one preterm infants were studied, of whom 144 were born to hypertensive mothers and 277 born to normotensive. The median for gestational age was 34 weeks in the 2 groups. The incidence of respiratory diseases was of 51%, without difference between groups. RDS occurred in approximately 30%, and transient tachypnea of the newborn in 15% of the studied sample. In multivariate analysis, the risk factors for RDS were: gestational age (OR= 0.5; CI95% 0.44 - 0.57); maternal hypertension (OR= 2.75; CI95% 1.41 - 5.34) and tocolysis (OR= 2.57; CI95% 1.08 - 6.10). Respiratory morbidity was high in the preterm infants, but it did not differ between the children of hypertensive and normotensive mothers. Hypertensive syndromes in pregnancy are a risk factor for RDS / Mestre

Ventilator associated pneumonia (VAP) and acute respiratory distress syndrome (ARDS) are two respiratory conditions unique to mechanically ventilated patients. The diagnosis of these conditions, and therefore any subsequent treatment, are befuddled by uncertainty. VAP rates vary considerably according to the diagnostic or surveillance criteria used. The pathogenesis of ARDS is well understood but when the internationally agreed consensus criteria are employed, the histological hallmarks are absent about half the time, indicating a disconnection between the clinical diagnosis and what is known about the biology of this condition. It is argued that tests of biological function should be considered in addition to clinical characteristics in order to improve the utility of diagnosis. Given that the pathological sequelae of both VAP and ARDS are driven by an over exuberant host neutrophil response, the activated neutrophil was selected as a potential biological imaging target. Optical molecular imaging uses visible and near visible wavelengths from the electromagnetic spectrum to derive or visualize information based on the optical properties of the target tissue. Optical wavelengths are safe and cheap to work with, producing much higher resolution images than those relying on x-rays or gamma radiation. The imaging modality can be coupled with exogenously applied chemistry to identify specific biological targets or processes. The hypothesis that optical molecular imaging could be used to detect activated neutrophils in real time in the alveolar region of patients was tested. A bespoke optical molecular imaging agent called Neutrophil Activation Probe (NAP), designed in-house, was used to test the hypothesis. NAP is a dendrimeric compound delivered to the alveolar region of a patient in microdoses (≤100 micrograms), becoming fluorescent only on contact with activated neutrophils, and can be detected by optical endomicroscopy. Both the imaging agent and the endomicroscope are delivered to the distal lung via routine bronchoscopy. The agent was tested extensively in the laboratory to demonstrate function, specificity, and safety. Ex vivo testing took place using human and ovine lungs. A regulated dose escalation Phase I clinical trial of investigational medicinal product (CTIMP) in healthy volunteers, patients with bronchiectasis, and mechanically ventilated patients with a pulmonary infiltrate on chest radiography (NCT01532024) was designed and conducted. The aim of the Phase I study was to demonstrate the safety of the technique and to confirm proof of concept. In order to support the requirement for a technique that interrogates alveolar neutrophils two supplementary clinical studies were performed. Firstly, two VAP surveillance techniques (CDC surveillance and HELICS European VAP surveillance) were compared with clinically diagnosed VAP across consecutive admissions in two large tertiary centres for one year. Secondly, the utility of circulating neutrophils to permit discrimination between acute respiratory illnesses was examined. Blood samples from mechanically ventilated patients with and without ARDS underwent flow cytometric assessment using eight clusters of differentiation and internal markers of activation to determine neutrophil phenotype. All clinical studies received the appropriate regulatory, ethical, and/or Caldicott guardian approval prior to commencement. NAP became fluorescent only in the presence of three processes specific to neutrophil activation: active pinocytosis, progressive alkalinization of the phagolysosome, and the activity of human neutrophil elastase. High optical signal was detected following the application of NAP in the alveolar regions of explanted lungs from patients with cystic fibrosis, known to be rich in activated neutrophils. Using an ex vivo ovine lung ventilation and perfusion model optical signal was demonstrated following segmental lung injury. The safety and specificity of the technique in a small cohort of healthy volunteers and mechanically ventilated patients was demonstrated. The technique was tested on a small cohort of patients with bronchiectasis, which provided the first opportunity to obtain broncho-alveolar lavage samples for laboratory correlation. Fluorescent signal was shown in the lavaged neutrophils, labeling that could only have taken place in the alveolar region. The supportive clinical studies found the concordance between actual VAP events was virtually zero even though the reported VAP rates were similar. Furthermore, the rate at which clinicians initiate antibiotics for VAP was approximately five times higher than either surveillance VAP rate. The study of circulating neutrophils from the blood of healthy volunteers and mechanically ventilated patients with and without ARDS indicated circulating neutrophil activation phenotype was not capable of discriminating between clinically diagnosed ARDS and other acute respiratory illnesses. In summary, an ambitious programme of work was completed to develop and support an optical molecular imaging technique that meets the rigorous requirements for human application and can be applied at the bedside to yield immediate visual results. The spatiotemporal relationship of neutrophil activation in real time both in the laboratory and in volunteers and patients was visualized. The visualization of neutrophil activation at such a resolution has never been achieved before in humans, healthy or unhealthy. The Phase I study was not powered to determine utility but recruitment has begun to a Phase II CTIMP (NCT02804854) to investigate the utility, accuracy, and precision of the imaging technique in a large cohort of mechanically ventilated patients. Ultimately, it is proposed that the technique will facilitate diagnosis, stratify patients for treatment and monitor treatment response using this technique.

Infecções por Plasmodium sp. podem levar a complicações pulmonares denominadas síndrome do desconforto respiratório agudo (SDRA). O modelo experimental, que utiliza o parasita murino Plasmodium berghei ANKA (PbA) e camundongos da linhagem DBA/2, é empregado no estudo de mediadores imunológicos e fatores que propiciam o estabelecimento das lesões pulmonares. Camundongos DBA/2 infectados com PbA foram classificados de acordo com a causa de morte como SDRA ou HP (hiperparasitemia). In vivo foi analisada a distribuição do parasita e os pulmões foram coletados para análise da capacidade respiratória, histopatologia, permeabilidade vascular, qRT-PCR e imunoistoquímica e efeito anti-inflamatório (Dexametasona - Dexa). In vitro, células endoteliais pulmonares foram submetidas a diversos estímulos. Verificamos que há acúmulo de PbA nos pulmões de DBA/2 com SDRA e que TNF e IFN-&#947; aumentam a citoadesão, expressão de ICAM-1, VCAM-1 e EPCR. A inibição de TNF diminui a adesão e dexa protege os animais através da diminuição de fatores inflamatórios, EPCR e inibição da abertura de junções interendoteliais. A intervenção da citoaderência e da permeabilidade vascular com o uso de corticosteróides, pode ser um importante alvo para o tratamento e a prevenção da SDRA. / Infections by Plasmodium sp. can lead to pulmonary complications called acute respiratory distress syndrome (ARDS). The experimental model, using the murine parasite Plasmodium berghei ANKA (PbA) and DBA/2 mice, is used no study of immunological mediators and factors that allow the establishment of lung lesions. DBA / 2 mice infected with PbA were classified according to cause of death as ARDS or HP (hyperparasitism). In vivo the parasite distribution was analyzed, and the lungs were collected for respiratory capacity analysis, histopathology, vascular permeability, qRT-PCR, immunohistochemistry and anti-inflammatory effect (Dexamethasone-Dexa). In vitro, pulmonary endothelial cells were submitted to various stimuli. We found that there is accumulation of PbA in the lungs of DBA/2 with ARDS and TNF and IFN-&#947; increase cytoadhesion, expression of ICAM-1, VCAM-1 and EPCR. Inhibition of TNF decreases adhesion and dexa protects animals by decreasing inflammatory factors, EPCR and inhibiting the opening of interendothelial junctions. The intervention of cytoadherence and vascular permeability with the use of corticosteroids may be an important target for the treatment and prevention of ARDS.

Immune cells such as neutrophils and monocytes enter tissues after tissue damage and clear cell debris to allow repair cells such as fibroblasts to close the wound. Monocytes also differentiate into fibroblast-like cells called fibrocytes to mediate wound healing, similar to fibroblasts. However, in abnormal wound healing such as acute respiratory distress syndrome (ARDS) and fibrosing diseases, the accumulation of immune cells such as neutrophils or fibrocytes become detrimental to health. In ARDS, neutrophils accumulate in the lungs and causes additional damage by producing reactive oxygen species (ROS). In fibrosing diseases, increased fibrocyte differentiation is one of the causes that increase extracellular matrix deposition, which leads to severe scar tissue build up. Since there are no effective treatments for ARDS or fibrosing diseases, understanding the regulation of neutrophil activation or fibrocyte differentiation could be helpful to develop new effective therapies. The Gomer lab has found several factors that either promote or inhibit fibrocyte differentiation. The pro-fibrotic cytokines such as IL-4 and IL-13 potentiate fibrocyte differentiation while the plasma protein serum amyloid P (SAP), crosslinked IgG, and the pro-inflammatory cytokines IFN-γ and IL-12 inhibit fibrocyte differentiation. In this thesis, I have now shown that additional factors such as toll-like receptor 2 (TLR2) agonists and low molecular weight hyaluronic acid (LMWHA) inhibit fibrocyte differentiation, while high molecular weight hyaluronic acid (HMWHA) potentiate fibrocyte differentiation. The accumulation of neutrophils in the lungs is one of the major factors that debilitate the health of a patient in ARDS. Since neutrophils have Fc receptors, I examined the effect of SAP on neutrophil spreading, adherence, activation, and accumulation. SAP inhibits neutrophil spreading induced by cell debris and TNF-α induced adhesion, but SAP is unable to have any effect on classic neutrophil adhesion molecules or the production of hydrogen peroxide. SAP inhibits neutrophil accumulation in the lungs of bleomycin-injured mice. There is an exciting possibility of using SAP as a therapeutic agent to treat ARDS.

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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Das akute Lungenversagen (Adult Respiratory Distress Syndrome: ARDS) stellt ein in der Intensivmedizin häufig auftretendes Krankheitsbild dar und weist trotz intensiver Bemühungen nach wie vor eine hohe Letalität auf. Ein wichtiger pathophysiologischer Faktor bei der mit dem ARDS verbundenen schweren Gasaustauschstörung ist der intrapulmonale Rechts-links-Shunt mit daraus resultierender Abnahme des Oxygenierungsindex. Um therapeutisch eine Verbesserung der Oxygenierung zu erreichen, wurde unter anderem von Gallart et al. ein Konzept entwickelt, bei dem durch den kombinierten Einsatz eines intravenös gegebenen pulmonalen Vasokonstriktors (Almitrine) und eines inhalativ gegebenen pulmonalen Vasodilatators (inhalatives Stickstoffmonoxid: iNO) die Shuntfraktion verkleinert wird (Gallart et al. 1998). Im Rahmen dieser Arbeit wurde die Kombination von iNO mit der intravenösen Gabe von zellfreiem Hämoglobin (Hemoglobin Based Oxygen Carrier, HBOC) als Vasokonstriktor am Tiermodell des akuten Lungenversagens hinsichtlich hämodynamischer Parameter und der arteriellen Oxygenierung untersucht. Die Ergebnisse wurden verglichen mit einer zweiten Versuchsgruppe, in der die Tiere lediglich iNO und Hydroxyethylstärke als Kontrollsubstanz erhielten. In Pilotversuchen wurden dafür ein Tiermodell des akuten Lungenversagens etabliert und die Auswirkungen der Gabe von HBOC bei vorbestehendem Lungenschaden untersucht. Anhand der durchgeführten Versuche konnte gezeigt werden, dass sich durch die HBOC-Gabe sowohl der systemische als auch der pulmonalarterielle Blutdruck signifikant erhöhte. Durch die zusätzliche Gabe von iNO ließ sich dieser Effekt antagonisieren. Ein additiver Effekt auf die arterielle Oxygenierung durch den kombinierten Einsatz von HBOC und iNO -im Vergleich zur alleinigen Gabe von iNO- war nachweisbar, die Unterschiede waren jedoch nicht signifikant. Weitere Untersuchungen werden zeigen müssen, ob sich dieser Effekt bei größerer Fallzahl als signifikant erweist, oder ob dieser tatsächlich nicht vorhanden sein sollte.