Thesis (M.A.)--University of Hong Kong, 1988. / Also available in print.

Submitted by Pós Imunologia (ppgimicsufba@gmail.com) on 2017-02-14T16:02:01Z No. of bitstreams: 1 Tese ELISABETE LOPES CONCEIÇÃO.pdf: 1470553 bytes, checksum: a38beb6dfeaae41d703bf5282cabb0a3 (MD5) / Approved for entry into archive by Uillis de Assis Santos (uillis.assis@ufba.br) on 2017-06-20T20:34:44Z (GMT) No. of bitstreams: 1 Tese ELISABETE LOPES CONCEIÇÃO.pdf: 1470553 bytes, checksum: a38beb6dfeaae41d703bf5282cabb0a3 (MD5) / Made available in DSpace on 2017-06-20T20:34:44Z (GMT). No. of bitstreams: 1 Tese ELISABETE LOPES CONCEIÇÃO.pdf: 1470553 bytes, checksum: a38beb6dfeaae41d703bf5282cabb0a3 (MD5) / Capes / O Mycobacterium tuberculosis e o vírus da imunodeficiência humana (HIV) agem em sinergia prejudicando a resposta imune para eliminação de ambos os patógenos. Fatores genéticos dos hospedeiros podem ser determinantes para o risco de progressão da tuberculose (TB) e infecção pelo HIV. Algumas variações genéticas têm sido associadas a diferenças no potencial para indução de apoptose e a alterações na produção de citocinas, tais como os polimorfismos de base única (SNPs) TNF-308G>A, DDX39B -22 G>C e -348C>T. Outra característica que acompanha a evolução da infecção é o estresse oxidativo sistêmico e o aumento da peroxidação. A Heme oxigenase-1 (HO-1) é o principal agente anti-oxidante expresso no tecido pulmonar, uma enzima de resposta ao estresse que degrada moléculas heme para a liberação de íons ferro, monóxido de carbono (CO) e biliverdina (BV). O presente trabalho propôs investigar fatores genéticos e imunológicos relacionados à imunopatogênese da TB e co-infecção TB-HIV. Para a realização do trabalho foram realizados: 1) uma revisão sistemática da literatura sobre os polimorfismos genéticos envolvidos nas vias e morte e associados com TB, 2) um estudo observacional de corte transversal para determinar a frequência de polimorfismos em voluntários monoinfectados com TB latente ou ativa e coinfectados com TB-HIV. Para este último foram recrutados 109 pacientes com tuberculose pulmonar (PTB), 60 pacientes coinfectados com HIV (TB-HIV) e 74 indivíduos com infecção tuberculosa latente (LTBI), e 3) Uma coorte avaliando os níveis de HO-1 e MMP-1 em pacientes com TB. Na revisão sistemática os polimorfismos dos genes do TNF, TNFR, IL-1 e P2RX7 estavam associados com tuberculose. No estudo de corte transversal a frequência do genótipo TNF-308G foi maior para o grupo LTBI comparado com TB e TB-HIV. A produção de TNF foi maior 8 entre os pacientes com PTB portadores do genótipo TNF -308GG. Os níveis de IL- 1α e IL-1β também foram mais elevados entre os pacientes com PTB portadores dos genótipos DDX39B -22CC e DDX39B -348CC. Não houve relação entre a produção de citocinas e a extensão da doença. Na coorte, os pacientes com TB apresentaram uma dicotomia na resposta de HO-1 MMP-1 com dois fenótipos, HO-1hiMMP-1lo e MMP-1 HO-1loMMP-1hi. Nosso estudo sugere que polimorfismos envolvidos na via de morte podem estar associados com susceptibilidade para o desenvolvimento da tuberculose, contudo, a frequência dos alelos e genótipos para os polimorfismos estudados não diferiram na co-infecção pelo HIV. O mecanismo entre o estresse oxidativo e remodelamento do tecido pode ter aplicabilidade clínica nos estágios da progressão da TB. / Mycobacterium tuberculosis and human immunodeficiency virus (HIV) act synergistically damaging immune response to eliminate both pathogens. Genetic factors of the host can be decisive for the risk of progression of tuberculosis (TB) and HIV infection. Some genetic changes have been associated with differences in potential for induction of apoptosis and changes in cytokine production such as single nucleotide polymorphisms (SNPs) TNF-308G> A, DDX39B -22 G> C and -348C> T. Another feature that monitors the infection is systemic oxidative stress and increased peroxidation. The heme oxygenase-1 (HO-1) is the primary anti-oxidant expressed in lung tissue, a response of the enzyme to stress that degrades heme molecules to the release of iron ions, carbon monoxide (CO), and biliverdin (BV) . This study proposed to investigate genetic and immunological factors related to TB immunopathogenesis and co-infection TB-HIV. To carry out the work were performed: 1) a systematic review of the literature on genetic polymorphisms involved in the pathways and death associated with TB, 2) an observational cross-sectional study to determine the frequency of polymorphisms in volunteers monoinfected with latent TB or active and co-infected with TB-HIV. For the latter were recruited 109 patients with pulmonary TB (PTB), 60 patients co-infected with HIV (HIV-TB) and 74 individuals with latent tuberculosis infection (LTBI), and 3) a cohort evaluating the levels of HO-1 and MMP- 1 in patients with TB. In the systematic review of TNF polymorphisms of genes, TNFR, IL-1 and P2RX7 were associated with tuberculosis. In the cross-sectional study the frequency of TNF-308G genotype was higher for LTBI group compared with TB and TB-HIV. The production of TNF was higher among patients with PTB patients TNF -308GG genotype. IL-1α and IL-1β were also higher among patients 10 with genotypes of PTB patients DDX39B -22CC and DDX39B -348CC. No relation between the production of cytokines and the extent of disease. In cohort, patients with TB presented a dichotomy in HO-1 MMP-1 response with two phenotypes, HO- 1hiMMP-1lo HO-1 and MMP-1loMMP-1hi. Our study suggests that polymorphisms involved in the death pathway may be associated with susceptibility to the development of tuberculosis, however, the frequency of alleles and genotypes for the studied polymorphisms did not differ in co-infection with HIV. The mechanism of oxidative stress and remodeling of the tissue may have clinical applicability in the progression of TB staging.

This thesis explores the effect that nationalism had on the spread of communism to Vietnam and Cuba during the first half of the twentieth century. Using a case studies approach to analyze the revolution of Ho Chi Minh in Vietnam and Fidel Castro in Cuba, the thesis seeks to determine the extent to which nationalism directed these revolutions and their turn to communism once assuming power. The study examines the conditions that existed in each country that allowed for a nationalist revolution to be successful, and the beliefs and rhetoric of Ho Chi Minh and Fidel Castro, the primary figures of each revolution. The thesis seeks to add to the research conducted on the power that nationalism had in the Third World from the early 1900s to 1960, and it wishes to contribute to the factors that must be considered by foreign policy makers when pursuing military action or nation-building abroad. The research shows that nationalism played a significant role in bringing communism to Vietnam and Cuba, yet due to the difficulty in measuring a core human feeling like nationalism, other factors cannot be discounted. / Master of Arts

Ein wesentliches Merkmal der Immundepression ist eine Monozytendeaktivierung mit verminderter Antigenpräsentation und Sekretion proinflammatorischer Zytokine. Infolge dessen sind Patienten mit Immundepression besonders anfällig gegenüber Infektionen. Als mögliche Mediatoren werden antiinflammatorische Zytokin wie IL10 und TGF-beta diskutiert, deren immunhemmende Wirkung allerdings nach Ihrem Entfernen schnell reversibel ist. An der Entwicklung einer langanhaltenden Immundepression müssen demnach weitere Mediatoren beteiligt sein. Eine Studie mit Patienten nach Herz-Operationen zeigte eine Korrelation zwischen einer erhöhten Anfälligkeit gegenüber Infektionen und einer Überexpression des Hitzeschockproteins Hämoxygenase-1 (HO-1) in peripheren Blutleukozyten, dem in vielen Studien eine antiinflammatorische und cytoprotektive Wirkung zugeschrieben wird. Eine Porphyrin-induzierte HO-1 Überexpression in humanen Monozyten korreliert mit einer verminderten MHC-II Expression. Allerdings kann eine Hemmung der HO-1-Expression diesen Effekt nicht aufheben, so dass die verwendeten Porphyrine die Antigenpräsentation durch HO-1-unabhängige Mechanismen beeinflussen müssen. Während sich die Hemmung der IFN-Gamma-induzierten MHC-II Expression durch eine gleichzeitig verminderte STAT-1-Phosphorylierung erklären lässt, ist die Porphyrin-induzierte Hemmung der konstitutiven MHC-II-Expression unabhängig von STAT-1. Zudem konnte weder eine Abhängigkeit von STAT-3, noch von einer verstärkten Histonacetylierung oder PKA-Aktivierung gezeigt werden. Die Ergebnisse deuten zudem darauf hin, dass die Porphyrin-Effekte nicht über eine Interaktion mit dem Hämoglobin-Scavenger Rezeptor CD163 induziert werden. Eine Porphyrin-Behandlung von Monozyten in vitro resultiert in einem ähnlichen Phänotyp, wie er in Monozyten von immundepressiven Patienten beobachtet wird, so dass ein verbessertes Wissen über die beeinflussten Signalwege neue Ansätze zur frühzeitigen Behandlung einer Immundepression liefern kann. / A long lasting immunodepression is characterised by a deactivation of the function of monocytes with decreased antigen presentation and decreased secretion of pro-inflammatory cytokines. This may predispose patients with immunodepression to infectious complications. Although anti-inflammatory cytokines as IL-10 and TGF-beta are discussed, the mechanism that induces and sustains this long lasting immunodepression is still incompletely understood. A previous study with patients after cardiac surgery could show a correlation between over expression of heme oxygenase-1 (HO-1) in peripheral blood leukocytes and an increased susceptibility to infection related complications. HO-1 is a stress-inducible heat shock protein with potent anti-inflammatory and cytoprotective properties. A porphyrin-induced HO-1 overexpression in human monocytes correlates with decreased MHC-II expression. However, inhibition of HO-1 expression does not abrogate this effect. According to this, porphyrins must affect the antigen presentation by HO-1-independent mechanisms. While the inhibition of IFN-Gamma-induced MHC-II expression could be explained by a simultaneously decreased STAT-1 phosphorylation, the porphyrin-induced inhibition of the constitutive MHC-II expression is independent of STAT-1. Moreover, neither STAT-3 activity, nor an increased histone acetylation or PKA activation is clearly involved in porphyrin mediated inhibition of MHC-II. The results further suggest that the porphyrin-effects are not induced by an interaction with the hemoglobin scavenger receptor CD163. Nevertheless a porphyrin-treatment of monocytes in vitro results in a similar phenotype, as observed in monocytes from patients with immunodepression. Therefore, better understanding of the involved pathways could reveal new approaches for the early treatment of patients with immunodepression.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The interest in antioxidants has increased considerably in recent years as molecules that reduce lipid peroxidation may minimize or inhibit the oxidative damage caused to DNA, proteins and carbohydrates. Flavonoids, a group of secondary metabolites widely distributed in the plant kingdom, have properties of anti-inflammatory, antibacterial, antiviral, anti-allergic and anti-tumor, in addition to possessing antioxidant and free radicals to inactivate them and prevent oxidative damage at cell level. It is believed that the biological activity of flavonoids is due to its antioxidant properties. Due to the great importance given today to free radicals and antioxidants, there is a strong demand for analytical techniques able to identify and quantify these two groups of compounds. This work describes the study of anti-radical power of the flavonoids kaempferol, fisetin, quercetin, quercitrin, myricetin and rutin against UV radiation and HO radical. The method used was based on artificial photochemical generation of HO radicals by photolysis of H2O2. The flavonoids studied were photpstable towards UV radiation and efficient in the fight against HO radical. The flavonoid quercitrin was the most active compound, followed by rutin, kaempferol, fisetin, quercetin and myricetin. The proposed methodology allows for quantitative comparison of the antiradical action of the antioxidants based on the reaction kinetics of the species with the HO radical. Similarly, the study in vitro the interaction between HO radicals and plant extracts with antioxidant character can be accomplished by the proposed method. / O interesse por substâncias antioxidantes aumentou consideravelmente nos últimos anos, pois moléculas que diminuem a peroxidação de lipídeos podem minimizar ou inibir os danos oxidativos causados ao DNA, proteínas e carboidratos. Os flavonóides, um grupo de metabólitos secundários, amplamente distribuídos no reino vegetal, apresentam propriedades antiinflamatórias, antibacterianas, antivirais, antialérgicas e antitumorais, além de possuírem propriedades antioxidantes sobre radicais livres de forma a inativá-los e a prevenir os danos oxidativos em nível celular. Acredita-se que a atividade biológica dos flavonóides seja devido às suas propriedades antioxidantes. Devido à grande importância dada atualmente aos radicais livres e antioxidantes, existe uma forte demanda por técnicas analíticas capazes de identificar e quantificar esses dois grupos de compostos. Este trabalho descreve o estudo do poder anti-radicalar dos flavonóides canferol, fisetina, quercetina, quercitrina, miricetina e rutina frente à radiação UV e ao radical HO . O método empregado baseou-se na geração fotoquímica artificial do radical HO pela fotodecomposição do H2O2. Os flavonóides estudados foram fotoestáveis frente à radiação UV e eficientes no combate ao radical HO . A quercitrina foi o flavonóide com maior ação anti-radicalar, seguida da rutina, canferol, fisetina, quercetina e miricetina. A metodologia proposta possibilita a comparação quantitativa da ação anti-radicalar de antioxidantes com base na cinética de reação das espécies com o radical HO . Da mesma forma, o estudo in vitro da interação entre radicais HO e extratos de plantas com caráter antioxidante pode ser realizado pelo método proposto.

No description available.

Participatory Action Research (PAR) was carried out to improve educational practices and environmental sustainability in an International School in Vietnam by undertaking two cycles of PAR to determine how the school community could use paper on a more sustainable basis. The methodology included sorting paper and encouraging the reuse of paper. Practices related to computer printing, report writing and newsletter production were also investigated. Changes in the school community, in terms of accepting responsibility and demonstrating changed attitudes and behaviours, were measured. The school community demonstrated greater awareness, increased responsibility and more action competence. Critical awareness of unsustainable practices increased. Individuals were able to effect change, but it is recommended that such actions should be institutionalised for such changes to be sustainable. Limitations and recommendations emphasise the need for continuing PAR to implement sustainability. / Educational Studies / M. Ed. (Environmental Education)

Participatory Action Research (PAR) was carried out to improve educational practices and environmental sustainability in an International School in Vietnam by undertaking two cycles of PAR to determine how the school community could use paper on a more sustainable basis. The methodology included sorting paper and encouraging the reuse of paper. Practices related to computer printing, report writing and newsletter production were also investigated. Changes in the school community, in terms of accepting responsibility and demonstrating changed attitudes and behaviours, were measured. The school community demonstrated greater awareness, increased responsibility and more action competence. Critical awareness of unsustainable practices increased. Individuals were able to effect change, but it is recommended that such actions should be institutionalised for such changes to be sustainable. Limitations and recommendations emphasise the need for continuing PAR to implement sustainability. / Educational Studies / M. Ed. (Environmental Education)

O gás monóxido de carbono (CO) possui diversas funções no sistema nervoso central (SNC) funcionando como neuromodulador, como por exemplo da regulação da temperatura corporal, da nocicepção e mais recentemente, do comportamento emocional. Este neuromodulador gasoso é produzido pela ação da enzima heme oxigenase (HO), a qual é encontrada em diferentes áreas do SNC. Com destaque, esta enzima tem alta expressão no locus coeruleus (LC), o que sugere o envolvimento do CO na modulação de funções desempenhadas por esta estrutura. O LC localiza-se na ponte, sendo a maior origem da inervação noradrenérgica do SNC. Esta estrutura tem participação ativa na modulação das respostas relacionadas ao estresse, em particular, na modulação do comportamento emocional, desde que integra o Sistema de Inibição Comportamental (SIC), o qual inclui ainda o sistema septo-hipocampal e os núcleos da rafe. O SIC é responsável por comandar respostas defensivas de avaliação de risco, alerta e atenção, as quais podem ser eliciadas pela ansiedade. Dentro desta perspectiva, o presente estudo teve como objetivo avaliar se a ativação sistêmica da via HO-CO pode modular o comportamento emocional de ratos, e se há participação do LC. Assim, este trabalho avaliou se o tratamento sistêmico via intraperitoneal (i.p.) agudo (3 h antes) ou crônico (10 dias/2 vezes ao dia) com um liberador de monóxido de carbono (CORM-2), ou com indutor da enzima HO (CoPP), altera as respostas comportamentais no teste do labirinto em cruz elevado (LCE) e no teste claro-escuro (TCE) em ratos, bem como a expressão da enzima HO no LC. Em uma segunda etapa foi avaliado se a administração aguda de CORM-2 ou CoPP altera o comportamento avaliado no LCE e no TCE de ratos submetidos ao estresse crônico variado (ECV) por 10 dias. Os resultados mostraram que o CO induzido pela administração aguda ou crônica de CORM-2 ou CoPP possui efeito ansiolítico. Ainda, o tratamento com CORM-2 ou CoPP aumentou a expressão da enzima HO-1 em células localizadas no LC, sem alterar a imunorreatividade à enzima HO-2. Considerando os grupos submetidos ao estresse ECV, nem a ativação da via HO-CO ou o ECV apresentaram efeitos significativos nos comportamentos avaliados nos testes LCE e TCE. Os resultados do presente estudo sugerem que o tratamento sistêmico com drogas que modulam a liberação de CO possui claro efeito ansiolítico. Assim, é possível que o CO possa ser uma droga com potencial terapêutico para o tratamento de desordens neuropsiquiátricas. / The carbon monoxide gas (CO) has several functions in the central nervous system acting as a neuromodulator, such as in the body temperature regulation, nociception and more recently, in the emotional behavior modulation. This gas is produced by the action of the heme oxigenase enzyme (HO), which is found in different areas of the central nervous system (CNS). It is important to note that this enzyme has high expression in the locus coeruleus (LC), suggesting the involvement of CO in the modulation functions performed by this midbrain structure. LC is located in the pons, being the source of majority of the noradrenergic innervation of the CNS. This structure is intimately involved in the stress modulation responses, particularly in the emotional behavior regulation, since it integrates the Behavioral Inhibition System (BIS), which also includes septum-hippocampal system and raphe nucleus. The BIS is responsible for defensive responses like the risk assessment and alertness trigged by anxiety. Within this perspective, the present study was designed to evaluate whether the systemic HO-CO pathway can modulate emotional behavior of rats, and if the HO enzyme of the neurons located into LC is involved in this response. Thus, this study evaluated whether the acute systemic i.p. treatment (3 hours before) or chronic (10 days / 2 times a day) with a carbon monoxide releaser (CORM-2) or inducer of heme enzyme oxygenase (CoPP), is able to alter the behavioral responses in the elevated plus maze (EPM) and in the light-dark box test (LDB) in rats, and the HO enzyme expression in the LC. Furthermore, the effect of the acute administration of CORM-2 or CoPP was evaluated in the emotional behavior assessed in the EPM and LDB by rats submitted to unpredictable chronic stress (during 10 days). The results showed that the CO induced by acute or chronic administration of CORM-2 or CoPP has an anxiolytic-like effect. Furthermore, treatment with CORM-2 or CoPP promoted an increase of HO-1 enzyme expression in cells located in the LC without altering the immunoreactivity of HO-2 enzyme. Still, considering the rats subjected to stress UCS neither the activation of HO-CO pathway nor the UCS protocol altered the emotional behavior evaluated in the EPM and LDB tests. The results of this study suggest that systemic treatment with drugs that modulate the CO release has anxiolytic effect. Thus, it is possible that CO can be a potential drug therapeutic target for neuropsychiatric disorders.

Die Schwangerschaft ist ein komplexer Vorgang, bei dem es zu einer Interaktion zwischen dem mütterlichen Immunsystem und dem Fetus kommt. Der allogene Fetus kann als natürlich auftretendes Allotransplantat angesehen werden. Man nimmt daher an, dass die Toleranzmechanismen, die im Rahmen einer erfolgreichen Schwangerschaft auftreten, den Mechanismen zur Akzeptanz eines Transplantates ähnlich sind. HO-1 wurde als ein gewebe-schützendes und anti-apoptotisches Molekül beschrieben, welches eine wichtige Rolle bei der Akzeptanz von Transplantaten spielt. Verschiedene Studien konnten zeigen, dass HO-1 in der Plazenta verschiedener Spezies exprimiert wird und dass die Expression von HO-1 bei Schwangerschaftskomplikationen, wie dem spontanen Abort, vermindert ist. Dies lässt vermuten, dass HO im Laufe der Schwangerschaft eine Rolle spielt. In diesem Kontext sollte die vorliegende Arbeit das Verständnis über die Funktion von HO-1 bei den beiden Schwangerschaftskomplikationen spontaner Abort und Präeklampsie (Schwangerschaftshypertonie) erweitern. Mit Hilfe des Mausmodells für einen spontanen Abort, bei dem weibliche CBA/J Mäuse mit männlichen DAB/2J Mäusen verpaart werden, wurde der Einfluss der HO-1 Expression auf die Abortrate untersucht und mit BALB/c-verpaarten CBA/J Weibchen, welche eine normale Schwangerschaft aufweisen, verglichen. In Mäusen mit spontanem Abort zeigte sich eine Reduktion der HO-1 und HO-2 Expression. Die Induktion von HO-1 mittels Co-PP war in der Lage, die Abortrate zu senken, wohingegen eine Reduktion der HO-1 mittels Zn-PP die Abortrate erhöhte. Es zeigte sich, dass es neben der Induktion von HO-1 auch zu einer erhöhten Expression des anti-apoptotischen Moleküls Bag-1 kam. Im Mausmodell für Präeklampsie wurde ebenfalls die Expression von HO-1 und möglicher Interaktionspartner untersucht. Des Weiteren wurde der Einfluss einer erhöhten bzw. verminderten HO-1 Expression auf die Präeklampsie-ähnlichen Symptome in diesem Mausmodell analysiert. Im Laufe der Arbeit zeigte sich jedoch, dass HO-1 Veränderungen keinen Einfluss auf die Präeklampsie-ähnlichen Symptome hat. Die Daten dieser Arbeit lassen vermuten, dass eine erhöhte Expression von HO-1 zum Zeitpunkt der Implantation den Fetus vor einem spontanen Abort schützt und dass die protektive Funktion von HO-1 durch eine Interaktion mit anti-apoptotischen Molekülen wird. Bei der Präeklampsie hingegen scheint HO-1 keine bzw. nur eine untergeordnete Rolle zu spielen. / Pregnancy maintenance is a very complex phenomenon, involving interactions between the maternal immune system and the semiallogenic foetus, which does not lead to immune rejection but to tolerance. Thus it is thought that the tolerance mechanisms involved in a successful pregnancy are closely related to those allowing graft acceptances. Heme Oxygenases (HO) were described to be tissue-protective and to have anti-apoptotic properties. Up-regulation of HO, particularly of HO-1, allows tissue tolerance after transplantation. The presence of HO-1 had been reported in the placenta of different species during normally progressing pregnancies; in pregnancy complications like spontaneous abortion the levels of HO-1 were reduced. This led to the proposal that HO-1 may play a protective role. The aim of this work was to analyze the influence of HO-1 changes in the outcome of pregnancy, using two different murine models for pregnancy complications, namely of spontaneous abortion and pre-eclampsia. The influence of HO-1 expression on the abortion rate was analysed in DBA/2J-mated CBA/J females, which spontaneously show high abortion rates compared to BALB/c-mated CBA/J females, having fully normal pregnancy. The induction of HO-1 by Co-PP led to diminished abortion rates, while the blocking of HO-1 and HO-2 by Zn-PP boosted abortion. In mice with reduced abortion rates after HO-1 induction, up-regulated levels of the anti-apoptotic molecule Bag-1 could be observed. In mice showing signs for preeclampsia after transfer of Th1 activated cells, the expression of HO-1, Th1/Th2 and eNOS was analysed. Furthermore HO-1 was of up- or down-regulated by using Co-PP or Zn-PP respectively. HO-1 changes did not influence the outcome of the disease, as we could not observe a diminution in the blood pressure levels. In summary, the results of this study indicate that high levels of HO-1 during implantation are able to prevent foetal rejection and that the beneficial effects of the HO-1 induction are related to the up-regulation of tissue protective molecules as Bag-1. No relationship could be observed between HO-1 levels and preeclampsia outcome.