A púrpura trombocitopênica idiopática (PTI) é uma patologia adquirida que leva à redução da contagem de plaquetas, mediada por mecanismo imunológico. O tratamento inicial é a corticoterapia e, se caracterizada a falência ou dependência desta, a esplenectomia é a segunda opção. Autores recomendam que a esplenectomia seja realizada antes de se completarem 12 meses do diagnóstico, apesar de estudos sugerirem que a resposta após este período é semelhante. Neste estudo, pesquisaram-se a eficácia da esplenectomia tardia, as complicações da manutenção da terapia imunossupressora e as complicações hemorrágicas na população com esplenectomia tardia. Analisaram-se prontuários de 39 pacientes com idade de 4 a 64 anos (mediana de 27 anos) ao diagnóstico, submetidos à esplenectomia como procedimento terapêutico de PTI. Classificaram-se as respostas à esplenectomia, observadas na última visita, após 6 meses da cirurgia, em resposta completa (RC) (mais de 150.000 plaquetas/ l) parcial (RP) (de 50.000 a 150.000 plaquetas/ l) ou sem resposta (SR) (menos de 50.000 plaquetas/ l ou necessidade de medicação para controle da PTI). No período anterior à esplenectomia, a prednisona causou efeitos colaterais em 18% dos pacientes. Uma paciente que utilizou azatioprina desenvolveu carcinoma ductal de mama. Outros efeitos colaterais da azatioprina, danazol, colchicina, levamisol e vincristina reverteram após a suspensão das drogas. Não houve mortalidade relacionada à PTI nem às esplenectomias, mas houve mais hemorragias graves (21%) no período pré-operatório. As esplenectomias foram realizadas após 1 a 174 meses (mediana 36 meses) do diagnóstico e a última visita ocorreu depois de 9 a 300 meses (mediana 25,5 meses) da cirurgia. As respostas finais à esplenectomia foram: 16 (44%) RC, 10 (28%) RP, 10 (28%) SR. A comparação entre as respostas dos pacientes que realizaram a esplenectomia antes e as dos que a realizaram após 36 meses não mostrou diferença significativa (p=0,687). A esplenectomia tardia tem eficácia, aferida pela soma das RC e RP, comparável à citada pela literatura. As medicações imunossupressoras produziram mais efeitos colaterais e ocorreram mais hemorragias graves do que as relatadas pela literatura. / Idiopathic thrombocytopenic purpura (ITP) is an acquired immunologic disorder associated with reduction of platelet count. The primary treatment is prednisone in the majority of cases, and if it fails or if there is a dependence of it, the splenectomy is performed. The surgery is usually indicated within 12 months after diagnosis because of presumed better results. Nevertheless, clinical studies suggest that splenectomy is effective when performed after this 12 months. In this study the hemorrhagic complications of ITP, the side effects of immunossupressive therapy during preoperative period and the efficacy and safety of the procedure were studied in a population with late splenectomy. Thirty nine patients were included with median age of 27 years (range 4 to 64 years) at the diagnosis of ITP. The response to splenectomy were classified as complete response (CR) (platelets counts above 150.000/ l), partial response (PR) (platelet counts of 50.000 to 150.000/ l), and no response (NR) (less than 50.000/ l or use of drugs to maintain platelet count). In the preoperative period, prednisone caused side effects in 18% of patients. One patient who received azathioprine had breast cancer. Other side effects of azathioprine, danazol, colchicin, levamisole and vincristine remitted after drugs withdrawal. The surgeries were performed after 1 to 174 months of diagnosis (median of 36 months). Of the 39 patients, 36 had assessment of response to splenectomy after 9 to 300 months: 16 patients had CR (44%), 10 PR (28%), and 10 NR (28%). The responses of the patients with period of diagnosis to splenectomy of 36 months or more were not different from the patients with this period of less than 36 months (p=0.687). During the preoperative period, 21% of patients had severe hemorrhagic complications of ITP, but there were no death caused by ITP or splenectomy. Although, the favorable response (sum of CR and PR) of late splenectomy was similar, there were more side effects of immunossupressive therapy and severe hemorrhagic complications than the reported in the literature. Splenectomy is a therapeutic option for immune thrombocytopenic purpura (ITP), usually recommend before 12 months after diagnosis. In this study, 39 patients were splenectomized 1 to 174 months (median of 36 months) after the hemorrages and more side effects of prednisone than reported in the literature, but there were death. The favorable responses of late splectomy were similar to the reported in the literature. the favorable responses of the group with period of ITP diagnosis to splenectomy of the 36 months or more were not different from the group with less than 36 months (p=0.687).

A púrpura trombocitopênica idiopática (PTI) é uma patologia adquirida que leva à redução da contagem de plaquetas, mediada por mecanismo imunológico. O tratamento inicial é a corticoterapia e, se caracterizada a falência ou dependência desta, a esplenectomia é a segunda opção. Autores recomendam que a esplenectomia seja realizada antes de se completarem 12 meses do diagnóstico, apesar de estudos sugerirem que a resposta após este período é semelhante. Neste estudo, pesquisaram-se a eficácia da esplenectomia tardia, as complicações da manutenção da terapia imunossupressora e as complicações hemorrágicas na população com esplenectomia tardia. Analisaram-se prontuários de 39 pacientes com idade de 4 a 64 anos (mediana de 27 anos) ao diagnóstico, submetidos à esplenectomia como procedimento terapêutico de PTI. Classificaram-se as respostas à esplenectomia, observadas na última visita, após 6 meses da cirurgia, em resposta completa (RC) (mais de 150.000 plaquetas/ l) parcial (RP) (de 50.000 a 150.000 plaquetas/ l) ou sem resposta (SR) (menos de 50.000 plaquetas/ l ou necessidade de medicação para controle da PTI). No período anterior à esplenectomia, a prednisona causou efeitos colaterais em 18% dos pacientes. Uma paciente que utilizou azatioprina desenvolveu carcinoma ductal de mama. Outros efeitos colaterais da azatioprina, danazol, colchicina, levamisol e vincristina reverteram após a suspensão das drogas. Não houve mortalidade relacionada à PTI nem às esplenectomias, mas houve mais hemorragias graves (21%) no período pré-operatório. As esplenectomias foram realizadas após 1 a 174 meses (mediana 36 meses) do diagnóstico e a última visita ocorreu depois de 9 a 300 meses (mediana 25,5 meses) da cirurgia. As respostas finais à esplenectomia foram: 16 (44%) RC, 10 (28%) RP, 10 (28%) SR. A comparação entre as respostas dos pacientes que realizaram a esplenectomia antes e as dos que a realizaram após 36 meses não mostrou diferença significativa (p=0,687). A esplenectomia tardia tem eficácia, aferida pela soma das RC e RP, comparável à citada pela literatura. As medicações imunossupressoras produziram mais efeitos colaterais e ocorreram mais hemorragias graves do que as relatadas pela literatura. / Idiopathic thrombocytopenic purpura (ITP) is an acquired immunologic disorder associated with reduction of platelet count. The primary treatment is prednisone in the majority of cases, and if it fails or if there is a dependence of it, the splenectomy is performed. The surgery is usually indicated within 12 months after diagnosis because of presumed better results. Nevertheless, clinical studies suggest that splenectomy is effective when performed after this 12 months. In this study the hemorrhagic complications of ITP, the side effects of immunossupressive therapy during preoperative period and the efficacy and safety of the procedure were studied in a population with late splenectomy. Thirty nine patients were included with median age of 27 years (range 4 to 64 years) at the diagnosis of ITP. The response to splenectomy were classified as complete response (CR) (platelets counts above 150.000/ l), partial response (PR) (platelet counts of 50.000 to 150.000/ l), and no response (NR) (less than 50.000/ l or use of drugs to maintain platelet count). In the preoperative period, prednisone caused side effects in 18% of patients. One patient who received azathioprine had breast cancer. Other side effects of azathioprine, danazol, colchicin, levamisole and vincristine remitted after drugs withdrawal. The surgeries were performed after 1 to 174 months of diagnosis (median of 36 months). Of the 39 patients, 36 had assessment of response to splenectomy after 9 to 300 months: 16 patients had CR (44%), 10 PR (28%), and 10 NR (28%). The responses of the patients with period of diagnosis to splenectomy of 36 months or more were not different from the patients with this period of less than 36 months (p=0.687). During the preoperative period, 21% of patients had severe hemorrhagic complications of ITP, but there were no death caused by ITP or splenectomy. Although, the favorable response (sum of CR and PR) of late splenectomy was similar, there were more side effects of immunossupressive therapy and severe hemorrhagic complications than the reported in the literature. Splenectomy is a therapeutic option for immune thrombocytopenic purpura (ITP), usually recommend before 12 months after diagnosis. In this study, 39 patients were splenectomized 1 to 174 months (median of 36 months) after the hemorrages and more side effects of prednisone than reported in the literature, but there were death. The favorable responses of late splectomy were similar to the reported in the literature. the favorable responses of the group with period of ITP diagnosis to splenectomy of the 36 months or more were not different from the group with less than 36 months (p=0.687).

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-06-14T19:33:16Z No. of bitstreams: 1 alicebelleigolirezende.pdf: 4554252 bytes, checksum: 45624650ab925d7640e01b2b01e2a245 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-06-29T12:16:33Z (GMT) No. of bitstreams: 1 alicebelleigolirezende.pdf: 4554252 bytes, checksum: 45624650ab925d7640e01b2b01e2a245 (MD5) / Made available in DSpace on 2017-06-29T12:16:33Z (GMT). No. of bitstreams: 1 alicebelleigolirezende.pdf: 4554252 bytes, checksum: 45624650ab925d7640e01b2b01e2a245 (MD5) Previous issue date: 2011-08-30 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / A aterosclerose é uma doença imune-inflamatória associada ao acúmulo de lípides na camada íntima das artérias. O baço desempenha uma importante função imunológica, mas a sua participação no desenvolvimento da aterosclerose permanece controversa. Considerando que a incidência de esplenectomias totais ainda é alta e que a doença aterosclerótica é prevalente, é de grande importância que se verifique se o tecido esplênico influencia no processo de aterosclerose. Neste trabalho, o impacto da esplenectomia no desenvolvimento da aterosclerose foi avaliado em camundongos deficientes em apoproteína E (apoE). Os animais foram divididos em dois grupos: grupo controle (CT), composto de camundongos deficientes em apoE submetidos a um procedimento cirúrgico simulado; e grupo esplenectomia total (ET), camundongos deficientes em apoE submetidos à esplenectomia total. Trinta dias após a cirurgia, os animais foram submetidos a uma dieta aterogênica enriquecida com 0,15% de colesterol. Após oito semanas, os animais foram eutanasiados e o sangue, o coração e a aorta foram submetidos à análise. Os níveis séricos de colesterol total e de anticorpos anti-LDL oxidada foram avaliados. As áreas de lesão aterosclerótica na raiz da aorta foram quantificadas por morfometria em cortes histológicos corados com hematoxilina-eosina. As lesões ateroscleróticas nas porções torácica e abdominal das aortas foram determinadas pela porcentagem da superfície luminal corada com Sudan IV em relação à área total do vaso. Os resultados mostraram que os níveis séricos de colesterol total não foram alterados pela esplenectomia e que os títulos de anticorpos IgG anti-LDL oxidada foram semelhantes entre os grupos. No entanto, foi observada uma maior porcentagem de lesões ateroscleróticas nas porções torácica e abdominal das aortas de animais esplenectomizados. Além disso, camundongos esplenectomizados apresentaram lesões ateroscleróticas na raiz da aorta significativamente maiores do que os animais controles. Estes dados indicam, em conjunto, que a esplenectomia está associada ao aumento das lesões ateroscleróticas em camundongos deficientes em apoE submetidos à dieta aterogênica, sugerindo um papel ateroprotetor do baço no modelo estudado. / Atherosclerosis is an inflammatory immune disease associated with lipid accumulation in the intima layer of arteries. The spleen plays an important immune function, but its influence in development of atherosclerosis remains unclear. Evaluation of the role of the spleen in atherosclerosis is justified due to the high frequency of total splenectomies and the high prevalence of atherosclerotic disease. In this work, the effect of splenectomy on the development of atherosclerosis in apolipoprotein E (apoE) deficient mice was investigated. ApoE deficient mice were divided into a sham-operated control group (CT) and a splenectomized group (SP). Thirty days after surgery, animals were fed a high fat western diet (with 0.15% cholesterol). After eight weeks, mice were euthanized and their blood, heart, and aorta were subjected to analysis. Total serum cholesterol and anti-oxidized LDL antibodies were measured. Atherosclerotic lesion areas in the aortic root were stained with hematoxylin-eosin and quantified by morfometry. The atherosclerotic lesions in the thoracic and abdominal portions of aorta were determined by assessing the percentage of the luminal surface area stained by Sudan IV. Levels of total serum cholesterol did not vary significantly after splenectomy. Anti-oxidized LDL IgG antibodies were similar between groups. However, compared to the control group, atherosclerotic area in the thoracic and abdominal portions of aorta were significantly increased in splenectomized mice. These data were confirmed by the larger lesions in the aortic root in splenectomized mice. These data indicate that splenectomy increases atherosclerotic lesions in apoE deficient mice fed an atherogenic diet, suggesting a atheroprotector role of the spleen.

Dissertation (Ph.D.)--University of South Florida, 2007. / Includes vita. Includes bibliographical references. Also available online.

Dissertation (Ph.D.)--University of South Florida, 2009. / Includes vita. Includes bibliographical references. Also available online.

Das humorale Immungedächtnis wird von reifen Plasmazellen des Knochenmarks vermittelt, welche bei Immunreaktionen aus aktivierten B-Lymphozyten gebildet werden. Dabei sind im Blut Plasmablasten als unmittelbare Vorläufer der Plasmazellen nachweisbar, die von dort aus in das Knochenmark einwandern. Anhand der durchflusszytometrischen Detektion spezifischer Plasmablasten gelang es hier, das simultane Auftauchen von Wellen neu generierter, migratorischer Plasmablasten und reifer, nicht-migratorischer Plasmazellen im Blut eine Woche nach einer Tetanusimpfung nachzuweisen. Plasmablasten und Plasmazellen lagen stets im Gleichgewicht vor, wodurch auf die stöchiometrische Mobilisierung reifer Plasmazellen des Knochenmarks durch systemisch induzierte Plasmablasten geschlossen wurde. Ein solcher Verdrängungsmechanismus wird hier erstmalig als Anpassungsmechanismus des humoralen Immungedächtnisses dargestellt, der die Aufnahme neuer Spezifitäten in das Gedächtnis unter Wahrung der Stabilität präexistierender Spezifitäten erlaubt. Anders als systemisch induzierte Plasmablasten, weisen Plasmablasten, die im immunologischen Ruhephase zirkulieren, Kennzeichen mukosaler Immunreaktionen auf: sie exprimieren IgA sowie die mukosalen Zellmigrationsrezeptoren alpha4beta7-Integrin und CCR10. Wahrscheinlich wandern sie in mukosale Plasmazelldepots ein und interferieren nicht mit den Plasmazellen des Knochenmarks, sodass die Stabilität des humoralen Gedächtnisses in der Ruhephase gewahrt bleibt. Eine Anpassung des humoralen Gedächtnisses findet somit nur im Rahmen systemischer Immunreaktionen statt. Bei splenektomierten Patienten und unter der B-Zell-Depletionstherapie bei Rheumapatienten bleiben mukosale Plasmablasten im Blut nachweisbar. Dies belegt deren autonome Bildung aus mukosalen, therapie-refraktären B-Zellen. Insgesamt wird hier eine bisher unbeachtete Komplexität menschlicher peripherer Plasmablasten und Plasmazellen und ihren Beziehungen zum humoralen Immungedächtnis dargestellt. / Humoral memory, i.e. persistence of specific antibody titers, is provided by plasma cells in the bone marrow, which are generated from activated B cells during immune responses. At this, immediate plasma cell precursors, the plasmablasts, migrate via the blood to the bone marrow. Using cytometric detection of antigen-specific plasmablasts, synchronous circulation of waves of recently generated, migratory plasmablasts and non migratory plasma cells with a mature phenotype was demonstrated one week after tetanus vaccination. Circulating plasmablast and plasma cell numbers were always in homeostasis, so that the stoichiometric mobilization of old bone marrow plasma cells by recently generated plasmablasts was hypothesized. This plasma cell replacement mechanism is herein described for the first time as an adaption mechanism of the humoral memory that allows incorporation of new antibody specificities while maintaining pre-existing ones. In immunological steady state, very low numbers of plasmablasts are detectable in any donor. These express IgA and receptors for mucosal homing, alpha4beta7 integrin and CCR10, and therefore most likely migrate into mucosal plasma cell depots and do not interfere with plasma cells of the bone marrow, preserving the stability of humoral memory during steady state. Hence, adaption of humoral memory is only possible during systemic immune reactions. Circulating mucosal plasmablasts produced during steady state remain detectable in patients with rheumatoid arthritis during B cell depletion therapy as well as in asplenic patients. Hence, this type of plasmablasts is self-sufficiently generated from mucosal B cells that are refractory to B cell depletion therapy. This work demonstrates a hitherto disregarded complexity of peripheral plasmablast and plasma cell subsets in healthy humans, with implications for the regulation of induction and maintenance of humoral memory.

Dissertation (Ph.D.)--University of South Florida, 2009. / Title from PDF of title page. Document formatted into pages; contains 164 pages. Includes vita. Includes bibliographical references.

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Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 187 pages. Includes vita. Includes bibliographical references.