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‣ Cyclosporine A enhances gluconeogenesis while sirolimus impairs insulin signaling in peripheral tissues after 3 weeks of treatment

Lopes, P. C.; Fuhrmann, A.; Carvalho, F.; Sereno, J.; Santos, M. R.; Pereira, M. J.; Eriksson, J. W.; Reis, F.; Carvalho, E.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Português
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Cyclosporine A (CsA) and sirolimus (SRL) are immunosuppressive agents (IA) associated with new-onset diabetes after transplantation (NODAT). This study aims to evaluate the effects of 3-weeks of treatment with either CsA (5 mg/kg BW/day) or SRL (1 mg/kg BW/day) on insulin signaling and expression of markers involved in glucose metabolism in insulin-sensitive tissues, in Wistar rats. Although no differences were observed in fasting glucose, insulin or C-peptide levels, both treated groups displayed an impaired glucose excursion during both glucose and insulin tolerance tests. These results suggest glucose intolerance and insulin resistance. An increase in glucose-6-phosphatase protein levels (68%, p < 0.05) and in protein-tyrosine phosphatase 1B (163%, p < 0.05), a negative regulator of insulin was observed in the CsA-treated group in the liver, indicating enhanced gluconeogenesis and increased insulin resistance. On the other hand, glucokinase protein levels were decreased in the SRL group (35%, p < 0.05) compared to vehicle, suggesting a decrease in glucose disposal. SRL treatment also reduced peroxisome proliferator-activated receptor γ coactivator 1 alpha protein expression in muscle (∼50%, p < 0.05), while no further protein alterations were observed in muscle and perirenal adipose tissue nor with the CsA treatment. Moreover...

‣ Post-transplantation osteoporosis

Kulak,Carolina A. Moreira; Borba,Victória Z. Cochenski; Kulak Júnior,Jaime; Campos,Denise Jonhsson; Shane,Elizabeth
Fonte: Sociedade Brasileira de Endocrinologia e Metabologia Publicador: Sociedade Brasileira de Endocrinologia e Metabologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/03/2010 Português
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Transplantation is an established therapy for many hematologic disorders as well as for end-stage diseases of the kidney, lung, liver, heart among others. Osteoporosis and a high incidence of fragility fractures have emerged as a complication of organ transplantation. Many factors contribute to the pathogenesis of osteoporosis following organ transplantation. In addition, most patients have some form of bone disease prior to transplantation, which is usually related to adverse effects of end-stage organ failure on the skeleton. This chapter reviews the mechanisms of bone loss that occur both in the early and late post-transplant periods including the contribution of immunosuppressive agents as well as the specific features of bone loss after kidney, lung, liver, cardiac and bone marrow transplantation. Prevention and treatment for osteoporosis in the transplant recipient will also be addressed.

‣ Bone disease after transplantation: osteoporosis and fractures risk

Kulak,Carolina A. M.; Borba,Victoria Z. C.; Kulak Júnior,Jaime; Custódio,Melani Ribeiro
Fonte: Sociedade Brasileira de Endocrinologia e Metabologia Publicador: Sociedade Brasileira de Endocrinologia e Metabologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/07/2014 Português
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Organ transplantation is the gold standard therapy for several end-stage diseases. Bone loss is a common complication that occurs in transplant recipients. Osteoporosis and fragility fractures are serious complication, mainly in the first year post transplantation. Many factors contribute to the pathogenesis of bone disease following organ transplantation. This review address the mechanisms of bone loss including the contribution of the immunosuppressive agents as well as the specific features to bone loss after kidney, lung, liver, cardiac and bone marrow transplantation. Prevention and management of bone loss in the transplant recipient should be included in their post transplant follow-up in order to prevent fractures.

‣ Refractory pemphigus vulgaris treated with rituximab and mycophenolate mofetil

Biot,Stephanie Del Rio Navarrete; Franco,Joanna Pimenta de Araujo; Lima,Ricardo Barbosa; Pereira,Henrique Novo Costa; Marques,Luiz Paulo José; Martins,Carlos José
Fonte: Sociedade Brasileira de Dermatologia Publicador: Sociedade Brasileira de Dermatologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2014 Português
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The main treatment for pemphigus vulgaris are systemic corticosteroids and immunosuppressive agents, but due to adverse reactions and therapeutic failure, new drugs such as rituximab and mycophenolate mofetil have been used. In this case report are described two cases of severe pemphigus vulgaris refractory to various treatments, with resolution after use of rituximab and mycophenolate mofetil, associated with corticosteroids. A higher-than-usual dose of rituximab was employed, without the occurrence of serious adverse reactions. Mycophenolate mofetil was added as adjunctive therapy due to lack of response to azathioprine.

‣ New immunosuppressive agents in pediatric transplantation

Nguyen,Christina; Shapiro,Ron
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2014 Português
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Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.

‣ Effect of Immunosuppressive Agents on Normal Phage-neutralizing Antibody in the Mouse

Karp, R. D.; Bradley, S. G.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1968 Português
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The actions of three immunosuppressive drugs on normal antibody synthesis in the adult mouse were determined. Inbred mice were given daily intraperitoneal injections of actinomycin D, uracil mustard, or cyclophosphamide for extended periods. The sera of treated and untreated mice were assayed for phage-neutralizing activity to monitor the effect of each drug on the amount of circulating normal antibody. Except for an initial decrease in titer of normal anti-phage MSP2 activity, actinomycin D had no significant effect on normal antibody activity. Uracil mustard caused alternating elevation and depression of normal antibody titers. Cyclophosphamide caused a prolonged depression of normal antibody. The response patterns to the three immunosuppressive agents were the same for both induced and normal antibody.

‣ Differences among immunosuppressive agents.

Hitchings, G H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //1982 Português
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Immunosuppressive agents have diverse (although often multiple) sites of action in the cell sequences that are involved in immune responses. New routes to selectivity are apparent at both the cellular and the biochemical level. Meanwhile, clinical work is finding new uses and more selective employment of the currently available agents.

‣ CB2 cannabinoid receptor agonist, JWH-015 triggers apoptosis in immune cells: Potential role for CB2 selective ligands as immunosuppressive agents

Lombard, Catherine; Nagarkatti, Mitzi; Nagarkatti, Prakash
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Cannabinoids are known to interact with CB1 and CB2 receptors expressed in the nervous and immune system, respectively and mediate a wide range of effects, including anti-inflammatory properties. However, cannabinoids that bind CB1 are also psychoactive thereby limiting their clinical use. In this study, we investigated the immunosuppressive properties of JWH-015, a synthetic CB2-selective agonist. We found that JWH-015 triggered apoptosis in thymocytes in vitro and inhibited the proliferative response of T and B cells to mitogens through induction of apoptosis. JWH-015 induced cross-talk between extrinsic and intrinsic pathways of apoptosis involving caspase-8, caspase-9, and caspase-3 as well as loss of mitochondrial membrane potential. Finally, administration of JWH-015 in vivo caused thymic atrophy, apoptosis, and decreased peripheral T cell response to mitogens. Together, this study suggests that CB2 selective agonists, devoid of psychotropic effect, may serve as novel anti-inflammatory/immunosuppressive agents.

‣ The modulation of B7.2 and B7.1 on B cells by immunosuppressive agents

Jirapongsananuruk, O; Leung, D Y M
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em /10/1999 Português
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Several recent studies demonstrate that B7.2, but not B7.1, play an important role in allergic inflammation and IgE production. Agents that down-regulate B7.2 may therefore be of benefit for the treatment of Th2-driven allergic diseases. Our current study was carried out to investigate the effect of immunosuppressive agents, cyclosporin A (CsA) and dexamethasone, on B7.2 and B7.1 expression on B cells stimulated with the superantigen, toxic shock syndrome toxin-1 (TSST-1). The analysis of B7.2 and B7.1 on the same cells by flow cytometry demonstrated that TSST-1 up-regulated B7.2+B7.1− but not B7.1+B7.2− on B cells in a dose-dependent fashion. CsA and dexamethasone significantly down-regulated B7.2+B7.1− but up-regulated B7.2−B7.1+ B cells in the presence or absence of TSST-1 (100 ng/ml). Interestingly, the combination of CsA and dexamethasone was much more potent in the inhibition of B7.2 expression than either of these agents alone. As CD40 is known to up-regulate B7.2 expression on B cells, the mechanism of B7.2 down-regulation by CsA and dexamethasone was further studied by investigating the effect of these agents on CD40 expression on B cells. TSST-1 significantly increased CD40 expression on B cells. However, the addition of CsA or dexamethasone significantly down-regulated CD40 expression. Anti-CD40 MoAb significantly reversed the effects of CsA or dexamethasone on B7.2 and B7.1 expression...

‣ Current use of immunosuppressive agents in inflammatory bowel disease patients in East China

Huang, Li-Juan; Zhu, Qin; Lei, Min; Cao, Qian
Fonte: The WJG Press Publicador: The WJG Press
Tipo: Artigo de Revista Científica
Português
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AIM: To investigate immunosuppressive agents used to treat inflammatory bowel disease (IBD) in East China.

‣ Potential of immunosuppressive agents in cerebral ischaemia

Gupta, Yogendra Kumar; Chauhan, Anjali
Fonte: Medknow Publications Publicador: Medknow Publications
Tipo: Artigo de Revista Científica
Publicado em /01/2011 Português
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Ischaemic stroke is a disorder involving multiple mechanisms of injury progression including activation of glutamate receptors, release of proinflammatory cytokines, nitric oxide (NO), free oxygen radicals and proteases. Presently, recombinant tissue plasminogen activator (rtPA) is the only drug approved for the management of acute ischaemic stroke. This drug, however, is associated with limitations like narrow therapeutic window and increased risk of intracranial haemorrhage. A large number of therapeutic agents have been tested including N-methly-D-aspartate (NMDA) receptor antagonist, calcium channel blockers and antioxidants for management of stroke, but none has provided significant neuroprotection in clinical trials. Therefore, searching for other potentially effective drugs for ischaemic stroke management becomes important. Immunosuppressive agents with their wide array of mechanisms have potential as neuroprotectants. Corticosteroids, immunophilin ligands, mycophenolate mofetil and minocycline have shown protective effect on neurons by their direct actions or attenuating toxic effects of mediators of inflammation. This review focuses on the current status of corticosteroids, cyclosporine A, FK506, rapamycin, mycophenolate mofetil and minocycline in the experimental models of cerebral ischaemia.

‣ Development and Use a Novel combined in-vivo and in-vitro Assay for Anti-inflammatory and Immunosuppressive Agents

Li, Tan; Chen, Hong; Mei, Xin; Wei, Na; Cao, Bo
Fonte: Shaheed Beheshti University of Medical Sciences Publicador: Shaheed Beheshti University of Medical Sciences
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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Contact hypersensitivity (CHS) mouse model induced by 2, 4-dinitrofluorobenzene (DNFB) is thought to be a T helper 1 (Th1)-dominant response and used for investigating anti-inflammatory and immunosuppressive agents. However, it is hardly used for screening large-scale drugs because of the large number of animals and complex mechanisms involved in-vivo. In this study, we focused on whether T lymphocytes from CHS mouse model could maintain the state of immune response in-vitro and explored a suitable time for drugs screening. The results showed that CD4+ T cells of CHS mice were higher compared with those in normal group. The expression of T-bet and GATA3 showed a Th1 shift and the levels of interleukin (IL)-2 and IL-4 also showed similar trend. Furthermore, IL-6 produced by T lymphocytes from CHS mice had a high level too. Then, we detected the effects of dexamethasone (DEX), cyclosporine A (CsA) and mycophenolate mofetil (MMF) on T lymphocytes in-vitro, and the data displayed that these immunosuppressive drugs could all inhibit the proliferation of T lymphocytes significantly. These findings suggested that T lymphocytes from CHS mice could mimic a similar immune response in-vitro, and it’s also a suitable method for screening anti-inflammatory and immunosuppressive agents.

‣ Novel immunosuppressive agents in kidney transplantation

Hardinger, Karen L; Brennan, Daniel C
Fonte: Baishideng Publishing Group Co., Limited Publicador: Baishideng Publishing Group Co., Limited
Tipo: Artigo de Revista Científica
Português
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Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been attained at many renal transplant centers using contemporary immunosuppressive, consisting of an induction agent, a calcineurin inhibitor, an antiproliferative agent plus or minus a corticosteroid. Despite improvements with these regimens, chronic allograft injury and adverse events still persist. The perfect immunosuppressive regimen would limit or eliminate calcineurin inhibitors and/or corticosteroid toxicity while providing enhanced allograft outcomes. Potential improvements to the calcineurin inhibitor class include a prolonged release tacrolimus formulation and voclosporin, a cyclosporine analog. Belatacept has shown promise as an agent to replace calcineurin inhibitors. A novel, fully-human anti-CD40 monoclonal antibody, ASKP1240, is currently enrolling patients in phase 2 trials with calcineurin minimization and avoidance regimens. Another future goal of transplant immunosuppression is effective and safe treatment of allograft rejection. Novel treatments for antibody mediated rejection include bortezomib and eculizumab. Several investigational agents are no longer being pursed in transplantation including the induction agents...

‣ New immunosuppressive agents in pediatric transplantation

Nguyen, Christina; Shapiro, Ron
Fonte: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Publicador: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
Tipo: Artigo de Revista Científica
Publicado em /01/2014 Português
Relevância na Pesquisa
47.705264%
Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.

‣ Suppression of NF-kappa B by Cyclosporin A and Tacrolimus (FK506) via Induction of the C/EBP Family: Implication for Unfolded Protein Response

Du, S.; Hiramatsu, N.; Hayakawa, K.; Kasai, A.; Okamura, M.; Huang, T.; Yao, J.; Takeda, M.; Araki, I.; Sawada, N.; Paton, A.; Paton, J.; Kitamura, M.
Fonte: Amer Assoc Immunologists Publicador: Amer Assoc Immunologists
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
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Immunosuppressive agents cyclosporin A (CsA) and tacrolimus (FK506) inhibit cytokine production by activated lymphocytes through interfering with calcineurin. However, little is known about their effects on the function of nonlymphoid cells. We found that, in renal tubular cells, induction of MCP-1 by inflammatory cytokines was blunted by CsA and FK506. This suppression was correlated with induction of unfolded protein response (UPR) evidenced by endogenous and exogenous indicators. The induction of UPR by these agents was reversible and observed generally in other nonimmune cells. Furthermore, administration with CsA in reporter mice caused rapid, systemic induction of UPR in vivo. In TNF--treated cells, suppression of MCP-1 by CsA or FK506 was associated with blunted responses of NF-B, the crucial regulator of MCP-1. The suppression of NF-B was reproduced by other inducers of UPR including AB5 subtilase cytotoxin, tunicamycin, thapsigargin, and A23187. CsA and FK506, as well as other UPR inducers, caused up-regulation of C/EBP family members, especially C/EBPβ and CHOP (C/EBP homologous protein), and overexpression of either C/EBPβ or CHOP significantly attenuated TNF--triggered NF-B activation. Furthermore, down-regulation of C/EBPβ by small interfering RNA substantially reversed the suppressive effect of CsA on TNF--induced MCP-1 expression. These results suggested that CsA and FK506 confer insensitiveness to TNF- on resident cells through UPR-dependent induction of the C/EBP family members; Shuqi Du...

‣ Increased levels of T cell granzyme b in bronchiolitis obliterans syndrome are not suppressed adequately by current immunosuppressive regimens

Hodge, S.; Hodge, G.; Ahern, J.; Liew, C.L.; Hopkins, P.; Chambers, D.; Reynolds, P.; Holmes, M.
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
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Bronchiolitis obliterans syndrome (BOS) is characterized by persistent alloreactive, infective and non-specific epithelial injury, loss of epithelial integrity and dysregulated repair. We have reported increased apoptosis of epithelial cells collected from the large airway in lung transplant recipients. As part of the alloreactive response, T cells induce apoptosis of target epithelial cells by secreting granzyme b. We hypothesized that granzyme b would be increased in lung transplant patients with acute rejection and BOS and that commonly used immunosuppressive agents would fail to suppress this serine protease adequately. We investigated intracellular T cell granzyme b in blood, bronchoalveolar lavage (BAL) and large airway brushing (23 controls, 29 stable transplant, 23 BOS, 28 acute rejection, 31 infection) using flow cytometry and assessed the effect of clinically relevant concentrations of cyclosporin A, tacrolimus, methylprednisolone and a protease inhibitor, gabexate mesilate, on in vitro granzyme b production. Granzyme b was increased significantly in all compartments of all transplant groups compared to controls. Surprisingly, granzyme b was even higher in patients with BOS than in patients with acute rejection. In longitudinal analysis in three patients...

‣ Untersuchungen über den Einfluss von immunsuppressiven Substanzen auf die Interaktion dendritischer Zellen mit Aspergillus fumigatus; Investigation of the Impact of Immunosuppressive Agents on the Interaction between monocyte derived dendritic cells and Aspergillus fumigatus

Mickan, Andreas Richard
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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Die invasive Aspergillose ist eine gefürchtete, oft letale Infektion bei immundefizienten Patienten. Um die Rolle unterschiedlicher Immunsuppressiva in der Pathogenese der invasiven Aspergillose näher zu beleuchten, wurden deren Effekte durch in vitro- Analysen untersucht. In Vorarbeiten konnte gezeigt werden, dass aus Monozyten generierte, unreife dendritische Zellen nach Inkubation mit Aspergillus-fumigatus-Präparationen in reife dendritische Zellen ausdifferenzieren. Um den Einfluss verschiedener Immunsuppressiva auf diese Ausreifungsreaktion zu untersuchen, wurde die Expression von Zelldifferenzierungsmarkern im Durchflusszytometer analysiert. Ferner wurde deren Einfluss auf die DC-vermittelte, für Aspergillus-fumigatus spezifische, Lymphoproliferation und die Zytokinsekretion (Interleukin 4 und Interferon gamma) der Lymphozyten näher bestimmt. Analysiert wurden die klinisch häufig eingesetzten Immunsuppressiva Dexamethason, Cyclosporin A, Rapamycin und FK 506. Nach Inkubation mit Aspergillus-fumigatus-Hyphen und dem Proteinpräzipitat (PPSAB) des Erregers konnte eine Ausreifungsreaktion mit gesteigerter Oberflächenexpression der Marker CD 80, CD 83, CD 86 und MHC-Klasse II nachgewiesen werden. Für die genannten Immunsuppressiva konnte eine konzentrationsabhängige Hemmung der DC-induzierten Aspergillus-fumigatus-spezifischen Lymphoproliferation gezeigt werden. Die Zytokinausschüttung IFN  in den Überständen wurde durch Cyclosporin A und Rapamycin unterdrückt. Für Interleukin-4 konnte nur unter Cyclosporin A eine geringe Unterdrückung der Ausschüttung gezeigt werden. Bei der Ausreifung dendritischer Zellen nach Inkubation mit Aspergillus-fumigatus-Antigenen bewirkte insbesondere Dexamethason eine Hemmung der DC-Ausreifung. Zusammenfassend konnte im Rahmen dieser Arbeit gezeigt werden...

‣ Visual loss resulting from immunosuppressive therapy in patients with syphilitic uveitis

Afonso,Vivian Cristina Costa; Nascimento,Heloisa; Belfort,Rubens M.; Sato,Emilia Inoue; Muccioli,Cristina; Belfort Jr.,Rubens
Fonte: Conselho Brasileiro de Oftalmologia Publicador: Conselho Brasileiro de Oftalmologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2015 Português
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ABSTRACT Permanent visual loss can be caused by improper use of immunosuppressive therapy in cases of uveitis without differential diagnosis of syphilitic uveitis. We present four cases of syphilitic uveitis that were incorrectly diagnosed as being secondary to rheumatic diseases and were subsequently treated with immunosuppressive therapy, leading to permanent visual loss. These cases highlight the importance of ruling out syphilis in the differential diagnosis of inflammatory ocular diseases before starting use of immunosuppressive therapy.

‣ Comparative study of ophthalmological and serological manifestations and the therapeutic response of patients with isolated scleritis and scleritis associated with systemic diseases

Sousa,Jacqueline Martins de; Trevisani,Virgínia Fernandes Moça; Modolo,Rodrigo Pilon; Gabriel,Luís Alexandre Rassi; Vieira,Luis Antonio; Freitas,Denise de
Fonte: Conselho Brasileiro de Oftalmologia Publicador: Conselho Brasileiro de Oftalmologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2011 Português
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INTRODUCTION: Scleritis is a rare, progressive and serious disease, the signs of which are inflammation and edema of episcleral and scleral tissues and is greatly associated with systemic rheumatoid diseases. PURPOSE: To perform a prospective and comparative study between ophthalmologic manifestations, serologic findings and therapeutic response of patients with isolated scleritis and scleritis associated with systemic rheumatoid disease. METHODS: Thirty-two outpatients with non-infectious scleritis were studied, from March 2006 to March 2008. The treatment was corticoid eye drops associated with anti-inflammatory agents, followed by systemic corticoids and immunosuppressive drugs if necessary, was considered successful after six months without scleritis recurrence. RESULTS: Fourteen of 32 patients had scleritis associated with systemic rheumatoid disease, of which nine had rheumatoid arthritis, two systemic lupus erythematosus, one Crohn's disease, one Behçet's disease and one gout. There were no difference in relation to involvement and ocular complications, there was predominance of nodular anterior scleritis and scleral thinning was the most frequent complication. The scleritis associated with systemic rheumatoid disease group had 64.3% of autoantibodies...

‣ New immunosuppressive agents in pediatric transplantation

Nguyen, Christina; Shapiro, Ron
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; Formato: application/pdf
Publicado em 01/01/2014 Português
Relevância na Pesquisa
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Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.