Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-10-11T13:25:57Z No. of bitstreams: 1 flavialiciarodriguesmagacho.pdf: 2211542 bytes, checksum: 17ff2c88b41d6fd8f0a559f9d79f8d7e (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-10-16T13:58:49Z (GMT) No. of bitstreams: 1 flavialiciarodriguesmagacho.pdf: 2211542 bytes, checksum: 17ff2c88b41d6fd8f0a559f9d79f8d7e (MD5) / Made available in DSpace on 2018-10-16T13:58:49Z (GMT). No. of bitstreams: 1 flavialiciarodriguesmagacho.pdf: 2211542 bytes, checksum: 17ff2c88b41d6fd8f0a559f9d79f8d7e (MD5) Previous issue date: 2018-07-12 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Introdução: a doença renal crônica destaca-se por afetar a vida de milhares de brasileiros e onerar os cofres públicos. Na fase terminal da doença, a sobrevivência do paciente é condicionada à realização de um tipo de terapia renal substitutiva. A literatura tem demonstrado ser o transplante renal a alternativa custo-efetiva dentre as terapias renais substitutivas, pois permite a reintegração do paciente às suas atividades cotidianas, aumentando a expectativa e qualidade de vida. Um fator que tem contribuído para o sucesso dos transplantes renais é o avanço tecnológico dos imunossupressores. Recomenda-se para o tratamento de manutenção dos transplantes renais a administração de esquemas tríplices de medicamentos, compostos por um esteroide mais dois medicamentos de classes farmacológicas distintas (inibidores da calcineurina ou antimetabólitos ou inibidores da rapamicina). Objetivo: avaliar o custo-efetividade da administração de tacrolimo com micofenolato de sódio e Prednisona (Grupo 1= 93 pacientes) comparado com a associação de tacrolimo com everolimo e Prednisona (Grupo 2= 91 pacientes), no tratamento de manutenção pós-transplante renal, em uma Unidade de Prática Integrada do Hospital Santa Casa de Misericórdia de Juiz de Fora, Minas Gerais. Material e métodos: para a análise farmacoeconômica dos esquemas imunossupressores foi utilizado o modelo estático, do tipo Árvore de Decisão. O modelo foi desenvolvido no software Treeage Suite 2011 e acompanhou uma coorte de pós-transplantados renais, estimando os benefícios clínicos em termos de sobrevida e incidência de eventos adversos (rejeição, doença/infecção por citomegalovírus, perda do enxerto e morte), bem como os custos associados aos regimes imunossupressores, na perspectiva do Sistema Único de Saúde. Resultados: a supremacia do everolimo em relação ao micofenolato de sódio se fez presente principalmente nos eventos relacionados à incidência de pacientes que apresentaram infecção ou doença decorrente por citomegalovírus (4,4% com everolimo versus 20,4% com micofenolato de sódio, p = 0,001). Na análise considerando sobrevida como desfecho, o Grupo 2 não pode ser considerado custo-efetivo quando comparado ao uso de Grupo 1, pois a razão de custo-efetividade incremental foi cerca de R$229.876,30, excedendo o limiar de custo-efetividade recomendado pela Organização Mundial da Saúde, três vezes o produto interno bruto brasileiro. Já na análise que diz respeito à incidência de eventos adversos, a razão de custo-efetividade incremental foi cerca de R$52.760,52, portanto, o Grupo 2 foi considerado custo-efetivo em relação ao Grupo 1. Conclusão: o regime imunossupressor contendo ácido micofenólico é ainda considerado o padrão-ouro para o tratamento de manutenção do transplante renal, no entanto, está associado a muitos efeitos adversos para os transplantados. Esse estudo desmistifica tal regime, à medida que o regime imunossupressor contendo everolimo apresentou-se custo-efetivo em relação ao micofenolato na análise feita a partir da incidência de efeitos adversos, bem como na redução significativa de eventos relacionados ao citomegalovírus, o qual é responsável pela maior causa de morbimortalidade em transplantados. / Introduction: chronic kidney disease stands out as affecting the lives of thousands of Brazilians and burdening the public coffers. In the terminal phase of the disease, the survival of the patient is conditioned to a type of substitutive renal therapy. The literature has demonstrated that kidney transplantation is the cost-effective alternative among the substitutive renal therapies, since it allows reintegration of the patient into their daily activities, increasing the expectation and quality of life. One factor that has contributed to the success of kidney transplantation is the technological advancement of immunosuppressants. The administration of three-drug regimens consisting of a steroid plus two drugs of different pharmacological classes (calcineurin inhibitors or antimetabolites or inhibitors of rapamycin) is recommended for the maintenance treatment of kidney transplantation. Aim: to evaluate the cost-effectiveness of administration of tacrolimus with mycophenolate sodium and prednisone (Group 1 = 93 patients) compared to the combination of tacrolimus with everolimus and Prednisone (Group 2 = 91 patients) in post-transplant renal maintenance, in an Integrated Practice Unit of the Santa Casa de Misericórdia Hospital of Juiz de Fora, Minas Gerais. Material and methods: for the pharmacoeconomic analysis of the immunosuppressive regimens, the static model, of the decision tree type, was used. The model was developed in the Treeage Suite 2011 software and followed a cohort of renal transplant recipients, estimating the clinical benefits in terms of survival and incidence of adverse events (rejection, cytomegalovirus disease / infection, graft loss and death), as well as the costs associated with immunosuppressive regimens, from the Unified Health System perspective. Results: the efficacy of everolimo in relation to mycophenolate sodium was mainly present in the events related to the incidence of patients who presented infection or disease due to cymegalovirus (4.4% with everolimo versus 20.4% with mycophenolate sodium, p = 0.001). In the analysis considering survival as an outcome, Group 2 can not be considered cost-effective when compared to Group 1 use, as the incremental Cost-Effectiveness Ratio was around R$229,876.30, exceeding the cost thresholdeffectiveness recommended by the World Health Organization, three times the Brazilian GDP. In the analysis related to the incidence of adverse events, the ICR was around R$52,760.52, therefore, Group 2 was considered cost-effective in relation to Group 1. Conclusion: the immunosuppressive regimen containing mycophenolic acid is still considered the gold standard for the maintenance treatment of kidney transplantation, however, is associated with many adverse effects for transplant recipients. This study demystifies this regimen, as the immunosuppressive regimen containing everolimo was cost-effective in relation to mycophenolate in the analysis made from the incidence of adverse effects, as well as in the significant reduction of events related to citamegalovirus, which is responsible the greatest cause of morbidity and mortality in transplant patients.

Abstract Both immunosuppressive and nifedipine medication have been associated with drug-induced gingival overgrowth. There are several hypothetical mechanisms for drug-induced gingival overgrowth, such as the influence of genetic predisposition, alterations in gingival tissue homeostasis, especially in the function of fibroblasts, and drug-induced action on growth factors. Clinical studies have also shown that, those with poor oral hygiene status drug-induced gingival overgrowth is more prevalent and severe than those with good oral hygiene status. The working hypothesis was that immunosuppressive medication and/or nifedipine medication affects inflammatory cell profile and mitotic activity of keratinocytes in human overgrown gingiva. We studied gingival samples, collected from nifedipine-medicated cardiac outpatients and immunosuppression-medicated organ-transplant recipients. Patients were placed into four groups: 1) the immunosuppression group, patients receiving cyclosporin-A (CsA), azathioprine (AZA) and prednisolone (Pred) 2) the immunosuppression plus nifedipine group, patients receiving CsA, AZA, Pred. and nifedipine 3) the nifedipine group patients receiving only nifedipine and 4) the non-medicated control group. All of the samples related to moderate to severe degrees of gingival overgrowth, covering half to two thirds of the clinical crown. The aim of the study was to investigate the occurrence of Langerhans cells, macrophages, mast cells and mitotic activity of keratinocytes in human drug-induced overgrown gingiva, and consequently to assess their possible role in the pathogenesis of drug-induced gingival overgrowth. We found that immunosuppressive medication increased the numbers of reparative macrophages (RM3/1) and decreased the numbers of tryptase- and chymase-positive mast cells (MCTC) cells. We have also shown that immunosuppressive and nifedipine medication decreased the numbers of Langerhans cells (CD1a) and increased the numbers of 27E10-macrophages parallelly. Additionally we found increase in the mitotic activity of gingival keratinocytes and even two-fold thickening of gingival epithelium in immunosuppressive and nifedipine medication-induced gingival overgrowth as compared with healthy gingiva. Immunosuppressive medication activated gingival epithelium (27E10 expression in gingival keratinocytes) more than nifedipine medication. In conclusion, our results suggest that gingival overgrowth among immunosuppressive- and nifedipine-medicated patients is related to alteration of tissue homeostasis. First, this suggestion is supported by changes found in the numbers of cells that directly affect connective tissue turnover, e.g. reparative macrophages (RM3/1) and mast cells. Changes in the numbers of these cells could alter the cytokine- and growth factor-profile, which affects fibroblast function. Secondly, we found changes in the numbers of cells involved in regulation of inflammation, e.g. Langerhans cells and monocytes as compared with healthy controls. Immunosuppressive medication could directly activate gingival keratinocytes. We suggest that our findings mainly reflect the effects of immunosuppressive medication, but the role of inflammation cannot be excluded. The changes observed above represent differences of the pathogenesis of drug-induced gingival overgrowth between immunosuppressive and nifedipine medication. It must be however remembered that drug-induced gingival overgrowth is a result of multicausal intrinsic and extrinsic factors. Age, gender, concomitant medication with multiple drugs, plaque accumulation, and genetic disposition are additional risk factors. The abnormal distribution of specific immune system cell subpopulations does not alone prove a functional relationship to gingival overgrowth.

Submitted in partial fulfillment of the requirements for the degree of Master of Health Sciences in Clinical Technology, Durban University of Technology, Durban, South Africa, 2017. / Introduction The prevalence of infertility is increasing at an alarming rate globally. Many couples are afflicted with infertility due to an array of diseases, trauma and psychological stresses. Renal disease is one such pathophysiological condition which is increasing amongst the younger age group. Often the progression of chronic renal disease leads to end stage renal failure that requires a renal transplantation. Post renal transplant, immunosuppressive agents are routinely prescribed to prevent allograft rejection. Immunosuppressive agents are potent drugs that can have deleterious side effects on semen parameters. However, the effects of the immunosuppressive agents on semen parameters in the literature are unclear and require further investigation. It is, therefore, important to assess the effects of immunosuppressive agents on semen, especially the three vital aspects of sperm concentration, motility and morphology which form the basis of male reproduction. Aims and Objectives of study This was a prospective observational study evaluating the effects of different immunosuppressive regimens on sperm parameters in post renal transplant male patients. The main aspects of semen parameters such as sperm concentration, motility and morphology that determine reproductive potential were assessed in the study patients and compared to the gold standard of semen analysis according to the World Health Organisation (WHO) reference values. Methodology Thirty-four renal transplant patients were recruited from the databases of both private nephrologists in the greater Durban area and the academic renal unit at Inkosi Albert Luthuli Central Hospital. Following bioethical approval and informed consent, patients were required to produce a semen sample by masturbation. A questionnaire documenting the patient’s lifestyle, aetiology of renal disease, transplant date and immunosuppressive duration and regimen were recorded. The semen samples were analysed comprehensively according to the protocol on semen analysis recommended by the WHO. This included the macroscopic investigation (volume, appearance, colour, viscosity, liquefaction time and pH) and microscopic evaluation (sperm concentration, total motility, morphology, IgG/IgA and vitality). Sperm concentration, total motility, morphology and vitality were examined and recorded in duplicate to strengthen the validity of the results. A biostatistician analysed the data and determined the statistical analysis. Descriptive statistics determined values of semen parameters in renal transplanted males and in each race demographic. The one sample t-test analysed the statistical significance between the mean study values and the WHO reference values. The effect of the immunosuppressive agent on semen parameters was determined using multiple linear regressions whilst ROC analysis determined the sensitivity and specificity of sperm concentration, total motility and morphology in predicting pregnancy from the patients that fathered children post renal transplant. Results The mean sperm concentration and morphology in the study patients were 14.0 mill/ml (95% Confidence Interval (CI) 10.2 – 17.7) and 3.3% (95% CI 2.7 – 3.9), respectively. Although values obtained were minimally lower than the WHO reference values, these results were within the 95% CI of the WHO guidelines. Motility evaluation revealed higher values of 43.2% (95% CI 36.6 – 49.7). In contrast, sperm vitality was considerably decreased, 47.5% (95% CI 40.6 – 54.4). All semen parameters exhibited no statistical significance (one sample t-test) when analysed against the WHO reference values except for sperm morphology, (p = 0.025; p< 0.05) which showed decreased morphology irrespective of immunosuppressive regimen. Semen volume 1.7 ml (95% CI 1.3 – 2.0) and pH 7.7 (95% CI 7.6 – 7.9) were both within the WHO guidelines. Descriptive statistics according to racial demographics showed no differences in semen values. An almost perfect linear relationship existed between total sperm motility and vitality (r = 0.967). Multiple linear regressions of duration and dosages of immunosuppressive drugs tacrolimus and mycophenolate mofetil, could not predict the effect of the immunosuppressive agents on sperm concentration, total motility and morphology. There was a significant difference in morphology between those with and without children post renal transplant. Those with children post renal transplant exhibited a higher morphology value, (p = 0.001; p< 0.05). Sensitivity and specificity analysis of the patients with children post renal transplant concluded that morphology is the most optimal indicator and predictor of pregnancy (AUC = 0.854). Tacrolimus was the common immunosuppressive agent used in the four patients that fathered children. This was more evident in patients that underwent therapy with Sirolimus followed by Cyclosporin A (CsA) and changed to Tacrolimus as the last immunosuppressive agent used for maintenance therapy. Conclusion The ability to procreate in renal transplanted males has become increasingly difficult and emotionally challenging. In this study sperm concentration and morphology of renal transplanted males exhibited parameters similar to the general fertile population. Total motility possessed a higher range of values in contrast to sperm vitality which showed a significant decrease from the WHO reference values. The effect of immunosuppressive treatment on semen parameters could not be clearly defined due to the number of immunosuppressive regimens that patients were subjected to intermittently resulting in small sample sizes within each immunosuppressive regimen grouping. The majority of patients underwent a triple maintenance therapy of tacrolimus, MMF and prednisone. The dosage and duration of these tacrolimus and MMF was inconclusive in determining a beneficial or detrimental relationship on semen parameters. Morphology was shown to be the most significant indicator in predicting pregnancy in patients that fathered children. Tacrolimus was a common immunosuppressive agent used in the majority of patients that fathered children. It may have protective effects on sperm parameters as shown in patients that fathered children. This was a study with a small sample size and further investigations are required in a larger cohort of patients to assess individualized effects of the different immunosuppressive agents on sperm parameters. / M

As infecções são a causa mais freqüente de morbidade e mortalidade observadas tanto aguda como tardiamente nos pacientes receptores de transplante pulmonar, o que pode estar diretamente relacionado a uma deficiência no transporte mucociliar do sistema respiratório. Nosso objetivo foi avaliar a influência de dois fatores envolvidos com o transplante pulmonar sobre o transporte mucociliar de ratos: a secção e anastomose brônquica e a imunossupressão pela ciclosporina A. Setenta e dois ratos foram distribuídos aleatoriamente em cinco grupos de acordo com: i) procedimento operatório e ii) terapia a que seriam submetidos. Os resultados mostram que houve uma diminuição significativa da Freqüência de Batimento Ciliar in situ, da Transportabilidade do Muco in vitro e da Velocidade de Transporte Mucociliar in situ medidos a partir do brônquio principal esquerdo dos ratos tratados com ciclosporina A (p<0,001). A Freqüência de Batimento Ciliar in situ dos brônquios operados mostrou-se diminuída também no grupo tratado com solução salina e sacrificado no 30º dia após a operação (p=0,001). Já a Velocidade de Transporte Mucociliar in situ mostrou uma diminuição significativa em todos os grupos submetidos à secção brônquica (p<0,001). Houve um efeito sinérgico entre a terapia com ciclosporina A e a secção brônquica, causando um prejuízo ao transporte mucociliar ainda maior do que quando analisados isoladamente. Concluímos que a Velocidade de Transporte Mucociliar in situ foi agudamente prejudicada após a secção brônquica e terapia imunossupressora pela ciclosporina A, havendo diminuição da freqüência de batimento dos cílios e alteração das propriedades viscoelásticas do muco respiratório. / Infections are the most common cause of early and late morbidity and mortality in lung transplant recipient, and can be directly related to impaired mucociliary transport. Our aim was to assess the influence of bronchial section and imunossupression on mucociliary transport in rats. Seventy two rats were randomly distributed in five groups according to i) surgical procedure and ii) drug therapy. There was a significant impairment on Ciliary Beating Frequency in situ, Mucus Transportability Rate in vitro and Mucociliary Transport Speed in situ from operated bronchus of cyclosporine A-treated rats (p<0.001). Ciliary Beating Frequency from operated bronchus was also impaired in saline-treated rats that were killed on 30th postoperative day (p=0.001). Mucociliary Transport Speed was impaired in all bronchi underwent to section (p<0.001). We conclude that bronchial section and cyclosporine therapy impaired all factors analyzed. Also there was a synergic effect between cyclosporine therapy and bronchial section on ciliary beating frequency.

Thesis (MScMedSc (Pathology. Medical Microbiology))--University of Stellenbosch, 2005. / The aim of this study was to investigate the anti-inflammatory and immunosuppressive effects of the synthetic progestins, MPA and NET-A on human cells in vitro. These injectable contraceptives are used extensively throughout the world, including Africa. The potential of these two synthetic hormones to have certain immunosuppressive and GC properties have previously been shown. Therefore, it was of concern to us to investigate whether these two hormones could possibly demonstrate any of these GC-like properties at contraceptive doses. This was achieved by determining the effects of these two synthetic hormones in vitro on certain immunologic parameters. Chapter 1 is a literature review on MPA, NET and GCs. This chapter starts with a short introduction that sets the scene. The mode of action, effectiveness, sideeffects as well as previously reported relevant data on both MPA and NET-A is portrayed in this review. Research on the known GC, Dex, is also included in the section dealing with GCs, because this synthetic hormone was used as a comparative GC in all our experiments. This chapter soon makes the reader realize how much evidence exists that indicate the possible immunosuppressive effects these two contraceptive hormones, in particular MPA, could have. The possible anti-inflammatory or pro-inflammatory effects of MPA and NET-A are investigated in Chapter 2. This was done in vitro by measuring the effects of these two synthetic hormones on the inflammatory markers, IL-6 and TNFα, by means of ELISA. In this chapter we demonstrate that MPA, even at contraceptive doses, exhibits significant anti-inflammatory properties on both cytokines tested, while NETA displayed considerably less anti-inflammatory tendencies. In its true antiinflammatory manner, we found that Dex significantly inhibited the release of both inflammatory markers from human monocytes. In Chapter 3, we investigated the effects of MPA and NET-A on the activation of human lymphocytes. This was achieved by flow cytometric measurement of the expression of the activation membrane marker CD69 by CD4 and CD8 T cells. Here we discovered that MPA had a very significant inhibitory effect on the activation of both CD4+ and CD8+ T cells, while NET-A only significantly inhibited the activation of CD8+ T cells. In addition, we found that the inhibition of CD4+ and CD8+ T cell activation by MPA was more or less the same as the known GC, Dex, and in some cases even more potent. Chapter 4 consists of an investigation of the effects of MPA and NET-A on the cytokines belonging to TH1 and TH2 subsets of CD4 T cells. This was achieved by determining whether MPA and/or NET-A targeted specific subsets of T helper cells by measuring the distinct regulatory cytokines, IFNγ and IL-4. The mechanism and role of the T helper subsets are discussed in the introduction of this chapter. Our results were portrayed as a ratio of TH2: TH1 on which the statistical analysis was done. In addition to the analysis done on the ratio, we analyzed the helper subsets separately in order to determine which subset(s) were influenced. The results of this chapter showed that neither MPA nor NET-A significantly affected either one of the helper subsets, while Dex significantly decreased this ratio. After our observed effects of MPA and NET-A on CD8 T cells, it became of interest in Chapter 5 to investigate the effects of these two synthetic hormones on the CD8 T cell-specific chemokine, RANTES. This was achieved by measuring the effects MPA and NET-A had on RANTES production in vitro by means of ELISA. Surprisingly, we discovered in this chapter that MPA and NET-A enhanced RANTES production before and after activation of CD8 T cells. We also found that Dex had the same effect on RANTES production, but to a lesser degree. Finally, a general conclusion depicting the significance and implications of our results as well as possible future research that is required is presented in Chapter 6. It was of great importance to discuss and interpret the magnitude of data generated out of all our experiments to the utmost of our capabilities. We found that MPA, even at contraceptive doses, displayed significant immunosuppressive as well as anti-inflammatory properties. NET-A, on the other hand, demonstrated weaker immunosuppressive properties in our research and no significant anti-inflammatory properties. These findings could have clinical implications in females being treated with these synthetic contraceptives. We also demonstrated significant variation found amongst genders in response to MPA, NET-A and Dex.

Introdução: Há poucos dados na literatura sobre a neuropatia periférica (NP) associada ao lúpus eritematoso sistêmico (LES). Objetivo: Descrever a NP atribuída exclusivamente ao LES e avaliar suas características clínicas, laboratoriais, tratamento e evolução a curto e longo prazo. Métodos: Pacientes com LES segundo critérios do American College of Rheumatology (ACR) de 1997, que tiveram NP sintomática comprovada por eletroneuromiografia foram identificados através de revisão do prontuário eletrônico. A NP foi classificada de acordo com a nomenclatura do ACR para síndromes neuropsiquiátricas do LES de 1999. Os critérios de exclusão foram qualquer outra condição clínica associada à ocorrência de NP: comorbidades, deficiência de vitamina B12, uso de drogas (álcool, talidomida, leflunomida, estatinas), infecções e outras doenças autoimunes. Controles com LES sem NP, pareados por idade e sexo, com duração de doença semelhante, foram selecionados. Resultados: NP devido exclusivamente ao LES foi identificada em 38 de 2074 pacientes (1,8%), sendo dois terços nos primeiros cinco anos da doença (63,2%). O tipo mais comum de NP foi a polineuropatia (71,1%), de padrão sensitivo-motor (68,4%). Pacientes com NP relacionada ao LES apresentaram maiores frequências de vasculite cutânea (50% vs. 21,1%, p=0,002), linfopenia (60,5% vs. 36,8%, p=0,027), anti-Sm (52,6% vs. 27,6%, p=0,013) e maiores escores de Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (11,5±10,5 vs. 4,9±6,7; p < 0,0001) comparados aos controles. Os escores de SLEDAI foram ainda mais altos em pacientes com início precoce da NP, com menos de um ano de diagnóstico da doença, comparados a pacientes com NP entre um e cinco anos e após cinco anos do início do LES (21,3±9,1 vs. 8,2±6,6 vs. 3,9±5,3; p < 0,001). Todos os pacientes com NP atribuída ao LES foram tratados com corticóides e 97,4% com terapia imunossupressora: ciclofosfamida intravenosa em 50% e azatioprina em 42,1% dos pacientes. Após um ano de acompanhamento, 92,1% dos pacientes apresentaram uma evolução favorável, com remissão total (36,8%) ou parcial (55,2%) do quadro neuropático, associada a redução da dose de prednisona (48,3±17,9 vs. 15,3±13,4mg/dia; p < 0,0001), da terapêutica sintomática (57,9% vs. 29,7%; p=0,02) e do escore SLEDAI (11,5±10,5 vs. 1,7±3,7; p < 0,0001). O grupo com início precoce da NP teve melhor resposta ao tratamento do que o grupo com início tardio (remissão completa após um ano: 61,5% vs. 25%, p=0,039). Após cinco anos de seguimento, 89,3% mantiveram remissão completa/parcial do quadro. Na análise multivariada, foi confirmada a associação significante entre NP e vasculite cutânea (OR 3,91; IC95% 1,59-9,54; p=0,003), anti-Sm (OR 2,77; IC95% 1,16-6,61; p=0,022) e linfopenia (OR 2,48; IC95% 1,05-5,89; p=0,039). Conclusão: a NP associada exclusivamente ao LES é uma manifestação incomum, caracterizada por um padrão bimodal, com um grupo de início precoce, associado a alta atividade de doença e maior taxa de remissão completa e um grupo de início mais tardio, com resposta parcial ao tratamento imunossupressor. Há um prognóstico geral favorável após um ano de tratamento, sem alterações significativas após cinco anos de seguimento / Introduction: There are few information in the literature regarding peripheral neuropathy (PN) associated to systemic lupus erythematosus (SLE). Objective: To describe PN attributed exclusively to SLE and evaluate its clinical, laboratorial characteristics, treatment, short and long-term outcome. Methods: SLE patients according to 1997 American College of Rheumatology (ACR) criteria were identified using an electronic medical record database. PN diagnosis was defined by neurological abnormalities associated with an altered electroneuromyography and classified according to 1999 ACR nomenclature for neuropsychiatric SLE syndromes. Clinical and laboratory data were evaluated at PN onset and after one and five years. Exclusion criteria were other conditions associated with PN: comorbidities, vitamin B12 deficiency, drugs (alcohol, thalidomide, leflunomide, statin), infections, and other autoimmune diseases. Age- sex- and disease duration-matched SLE patients without PN were selected as controls. Results: Lupus PN was identified in 38 of 2,074 patients (1.8%) and almost two-thirds had PN onset in the first five years of disease (63.2%). The most common type was polyneuropathy (71.1%) with sensory-motor pattern (68.4%). PN SLE had higher frequencies of cutaneous vasculitis (50% vs. 21.1%, p=0.002), lymphopenia (60.5% vs 36.8%, p=0.027), anti-Sm (52.6% vs. 27.6%, p=0.013) and higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (11.5±10.5 vs. 4.9±6.7, p < 0.0001) compared to controls. SLEDAI scores were higher in patients who had PN with less than one year of disease diagnosis, compared to those with PN onset between one and five years or more than five years of SLE (21.3±9.1 vs. 8.2±6.6 vs. 3.9±5.3; p < 0.001). At PN diagnosis, all patients received glucocorticoids and 97.4% started immunosuppressive therapy (50% intravenous cyclophosphamide, 42.1% azathioprine). After one-year follow-up, 92.1% had a favorable outcome with complete (36.8%) or partial remission (55.2%), in parallel with a decrease in prednisone dose (48.3±17.9 vs. 15.3±13.4mg/d, p < 0.0001), symptomatic therapy (57.9% vs. 29.7%, p=0.02), and SLEDAI scores (11.5±10.5 vs. 1.7±3.7, p < 0.001). Early PN onset group had a better response to treatment compared to late PN onset (complete remission at one-year follow-up 61.5% vs. 25%, p=0.039). At five-year, 89.3% remained with complete/partial remission. In multivariate analysis, PN was associated to cutaneous vasculitis (OR 3.91; 95%CI 1.59-9.54; p=0.003), anti-Sm (OR 2.77; 95%CI 1.16-6.61; p=0.022), and lymphopenia (OR 2.48; 95%CI 1.05-5.89; p=0.039). Conclusion: PN attributed to SLE itself is a rare manifestation with a bimodal pattern, characterized by an early onset group associated with high disease activity and a higher rate of complete remission, and a late onset group with low disease activity and a partial therapy response. This study reveals a favorable outcome after one year of immunosuppressive therapy in most PN SLE patients, without significant changes at five years of follow-up

Lic. -avh. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 3 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 6 uppsatser.

Dissertation (Ph.D.)--University of South Florida, 2006. / Includes vita. Includes bibliographical references (leaves 86-105). Also available online.

Orientadores: Mary Anne Heidi Dolder, Sebastiâo Roberto Taboga / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-17T18:35:57Z (GMT). No. of bitstreams: 1 Freitas_KarineMoura_M.pdf: 32609387 bytes, checksum: b57920281a8b30d840a5b4ab35a6557e (MD5) Previous issue date: 2011 / Resumo: A Ciclosporina A (CsA) é um imunossupressor amplamente utilizado no tratamento pós-transplante de órgãos e contra doenças auto-imunes. Entretanto, diversos efeitos colaterais estão relacionados ao tratamento com esta droga, dentre eles nefrotoxicidade, hepatoxicidade, tremor, hipertensão, hiperlipidemia, hipercalcemia, hipertricose e hiperplasia gengival. Além destes, danos à reprodução masculina como redução na produção de testosterona e disfunção testicular são extensivamente documentados. Heteropterys aphrodisiaca é uma planta arbustiva típica do Cerrado brasileiro. É conhecida como nó-de-cachorro, sendo utilizada popularmente como tônica e afrodisíaca. Estudos anteriores confirmam a eficiência da infusão de H. aphrodisiaca contra os efeitos colaterais a CsA nos testículos. Visto isso, o objetivo do presente trabalho foi determinar os possíveis efeitos colaterais da CsA na próstata ventral de ratos Wistar e verificar se a infusão de H. aphrodisiaca seria eficiente em minimizá-los. Trinta ratos Wistar adultos (90 dias) foram divididos em cinco grupos (n=6 em cada): Grupo I (controle): tratado com água; grupo II: tratado com CsA; grupo III: tratado com infusão de H. aphrodisiaca; grupo IV: tratamento simultâneo de CsA e H. aphrodisiaca; e grupo V: tratamento com CsA e H. aphrodisiaca em dias alternados. A CsA foi administrada na dose de 15 mg/kg/dia e a infusão de nó-de-cachorro no volume de 0,5 ml por animal (infusão preparada com 25 g de raiz seca e moída em 100 ml de água fervida). Todos os tratamentos foram realizados diariamente, durante 56 dias. Após este período os animais foram pesados e eutanasiados. Testículo, epidídimo, glândula vesicular, glândula de coagulação e próstata ventral foram coletados e pesados. A próstata ventral foi dividida em três porções. Uma foi fixada em Karnovsky e processada para inclusão em metacrilato; este material foi utilizado para análises morfológicas, morfométricas e estereológicas do tecido. A segunda porção, também fixada com Karnovsky, foi processada para inclusão em Epon; este material foi utilizado para realização de análises em microscopia eletrônica de transmissão. Por fim, a terceira porção foi fixada em Metacarn e incluída em parafina para realização de imunohistoquímica para detecção de receptor de andrógeno e técnica para detecção de apoptose (TUNEL). As análises morfológicas, morfométricas, estereológicas e ultraestruturais mostraram que o tratamento com a infusão de H. aphrodisiaca não causou nenhuma alteração na próstata ventral. Por outro lado, o tratamento com CsA causou severos danos a este tecido como redução nos volumes de lumen, epitélio, estroma muscular e não muscular, além de atrofia do epitélio. A análise ultraestrutural mostrou que nas células do epitélio atrofiado havia redução das organelas relacionadas à secreção de proteínas (retículo endoplasmático rugoso e complexo de Golgi), o que provavelmente leva à diminuição de sua atividade secretora. O tratamento conjunto de CsA e H. aphrodisiaca aparentemente reduziu os danos causados na próstata, o que foi evidenciado pela normalização nos parâmetros analisados que haviam sido prejudicados pela administração somente da CsA. Nenhuma alteração entre os grupos experimentais foi observada no padrão de marcação imunohistoquímica para receptores de andrógeno e no índice apoptótico. Os resultados obtidos mostram que o tratamento com CsA causa danos na estrutura prostática que provavelmente refletem em danos funcionais ao tecido. Além disso, foi confirmada a ação protetora da infusão de H. aphrodisiaca contra os efeitos colaterais da CsA na próstata ventral de ratos Wistar / Abstract: Cyclosporin A (CsA) is an immunosuppressive drug widely used in the post-operative treatment after organ transplants and against auto-immune diseases. However, various side effects have been associated with the use of this drug, including nephrotoxicity, hepatotoxicity, tremors, hypertension, hyperlipidemy, hypercalcicity, hypertrichosia and hyperplasticity of the gums. Besides these, damage to the male reproductive system, such as diminished testosterone production and testicular dysfunction, have been extensively documented. Heteropterys aphrodisiaca is a bush, typical of the Brazilian "Cerrado" region. It is known as "nó-de-cachorro" and used in traditional medicine as a tonic and an aphrodisiac drink. Previous studies confirm the efficiency of H. aphrodisiaca against the side effects of CsA in rat testicles. As a consequence, this research was undertaken with the aim of determining the possible collateral effects of CsA in the ventral prostate of Wistar rats and to verify whether the infusion of H. aphrodisiaca would be efficient to diminish the possible collateral effects of CsA in this organ. Thirty adult Wistar rats (90 days old) were divided into five groups (n=6 in each). Group I (control) was treated with water, Group II with CsA, group III received the H. aphrodisiaca infusion, group IV was treated simultaneously with CsA and H. aphrodisiaca infusion and group V received CsA or H. aphrodisiaca infusion on alternate days. CsA was administered in the dose of 15 mg/kg/day and the infusion in a volume of 0.5 ml per animal (infusion prepared with 25 g of dry ground roots in 100 ml of boiling water). All treatments were given daily for 56 days. After this period the rats were weighed and euthanized. Testis, epididymis, vesicular gland, coagulating gland and the ventral prostate were collected and weighed. The ventral prostate was divided into three portions. One was fixed in Karnovsky fixative and processed for inclusion in methacrylate. This portion was used for morphological, morphometrical and stereological analysis of the tissue. A second portion, fixed in the same manner, was processed for inclusion in Epon and analyzed with the transmission electron microscope. The last portion was fixed in Metacarn and included in paraffin to be used for immunohistochemistry of the androgen receptor and the TUNEL technique for apoptosis. The morphological, morphometrical, stereological and ultrastructural analyses showed that the H. aphrodisiaca infusion did not cause any alteration of the prostatic tissue. On the other hand, CsA treatment resulted in severe damage to the tissue, reducing the lumen, epithelium, muscular and non-muscular stroma. Atrophied epithelium was observed after CsA administration. Ultrastructural analysis showed that the atrophied epithelium had reduced organelles involved in protein secretion (rough endoplasmic reticulum and Golgi complex) which probably causes decreased secretory activity of the cells. The simultaneous treatment of CsA and H. aphrodisiaca apparently reduced the prostatic damage, since these were less damaged when compared to the prostate of animals that received only CsA. No alteration was found in the pattern of immunohistochemical labeling for androgen receptors and the apoptotic index, for all experimental groups. The results showed that CsA treatment caused structural damage to the prostate which probably reflected functional damage to the organ. The protective action of the H. aphrodisiaca infusion against the collateral effects of CsA was also confirmed for this organ. / Mestrado / Biologia Celular / Mestre em Biologia Celular e Estrutural