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Tay-Sachs disease, or GM2 gangliosidosis, is a congenital and neurodegenerative disease caused by the absence or deficiency of the essential enzyme B-hexosaminidase. The timing of the development of neurological manifestations and their severity depend on the mutation, time since disease onset and the patient's characteristics. The disease impairs quality of life and increases mortality. In the most aggressive forms, life expectancy is 3 years. Despite various clinical trials and ongoing research, there is currently no cure for Tay-Sachs disease. Treatment focuses on symptom control and ensuring greater patient wellbeing. Consequently, rehabilitation plays a fundamental role in the management of these patients and in enhancing their quality of life.
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Doenças Neurodegenerativas , Doença de Tay-Sachs , Humanos , Mutação , Qualidade de Vida , Doença de Tay-Sachs/genética , beta-N-Acetil-Hexosaminidases/genéticaRESUMO
The mechanisms that drive systemic lupus erythematosus (SLE) patients to achieve remission are unknown; one possible explanation might be T cell exhaustion. The aim of the present study was to measure CD4+ and CD8+ T cell exhaustion in SLE patients in prolonged remission (PR-SLE) and compared them with patients with active SLE (Act-SLE) and healthy subjects. We included 15 PR-SLE patients, 15 Act-SLE and 29 healthy subjects. T cell exhaustion was determined by flow cytometry according to the expression of programmed cell death 1 (PD)-1, T cell immunoglobulin and mucin 3 (Tim-3), natural killer cell receptor (2B4), eomesodermin (EOMES) and T-box transcription factor TBX21 (T-bet) in CD4+ and CD8+ T cells. Dimensionality reduction using the T-distributed stochastic neighbor-embedding algorithm and clustering analysis was used for the identification of relevant populations. Percentages of CD3+ , CD4+ and CD8+ T cells were similar among groups. We identified five subpopulations of CD8+ and seven of CD4+ cells. The CD4+ T-bet+ CD45RO+ cells identified in the unsupervised analysis were significantly increased in PR-SLE versus Act-SLE [median = 0·20, interquartile range (IQR) = 1·74-30·50 versus 1·68, IQR = 0·4-2·83; P < 0·01]. CD4+ EOMES+ cells were also increased in PR-SLE versus Act-SLE (5·24, IQR = 3·38-14·70 versus 1·39, IQR = 0·48-2·87; P < 0·001). CD8+ EOMES+ cells were increased in PR-SLE versus Act-SLE (37·6, IQR = 24·9-53·2 versus 8·13, IQR = 2·33-20·5; P < 0·001). Exhausted and activated T cells presented an increased frequency of PD-1, CD57 and EOMES in SLE patients versus healthy subjects. Some subpopulations of T cells expressing markers associated with exhaustion are increased in patients in remission, supporting T cell exhaustion as a tolerance mechanism in SLE. Exhaustion of specific populations of T cells might represent a potential therapeutic tool that will contribute to the goal of achieving sustained remission in these patients.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Biomarcadores/sangue , Estudos Transversais , Feminino , Citometria de Fluxo/métodos , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
The original published version of the above article contained errors in Key Points and Conclusion sections.
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OBJECTIVE: To describe the clinical and serological characteristics of patients with SLE who reached a state of sustained remission for more than 10 years in the absence of treatment. METHODS: From a retrospective cohort of 2121 patients, 44 cases with sustained remission (PtRem) were identified and compared with 88 patients whose course has been chronically active (PtAct).The clinical and serological characteristics were analyzed, as well as the treatment of each group at the beginning of the disease and during its evolution. RESULTS: Older age at disease onset was associated with a tendency to reach a state of prolonged remission. These patients also had a higher frequency of thrombocytopenia at the beginning of the disease 34.1% vs 10.2% (p < 0.001). PtAct had a significantly higher initial SLEDAI compared with cases (10.4 ± 5.6 vs 14.1 ± 5.8; p < 0.001). PtRem had a higher initial frequency of anti-ß2 GP1 IgG antibodies. Also, 25% of these patients were serologically active. We did not find differences in the initial treatment between both groups. The accumulated damage measured by SLICC/ACR damage index at the end of the study was significantly less in the patients who remained in prolonged remission. CONCLUSIONS: Although patients with SLE who achieve prolonged remission have some different characteristics at baseline compared with PtAct, it is not possible to identify a characteristic phenotype for the former. Achieving a state of prolonged remission should always be the goal in patients with SLE. Key Points ⢠SLE patients can reach a very prolonged state of remission, free of treatment, including antimalarials, for at least 10 years. ⢠Venous thromboembolism and thrombocytopenia are commonly present in patients that achieved remission. ⢠The presence of serological markers of activity, even after 10 years in remission, is a risk factor for relapse.
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Lúpus Eritematoso Sistêmico , Idoso , Estudos de Coortes , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Indução de Remissão , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
AIM: 18-Fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET/CT) is considered to be the most accurate image method of detection of node or distant metastases in cervical cancer. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of 18F-FDG PET/CT are volumetric measurements of tumor cells with increased 18F-FDG uptake. The prognostic value of MTV and TLG in patients with advanced cervical cancer (ACC) were evaluated. METHODS: 38 patients with ACC from one tertiary university hospital underwent 18F-FDG PET/CT between June 2009 and December 2015. Clinicopathologic factors and various PET parameters were analyzed to evaluate their relationship with recurrence-free survival (RFS) and overall survival (OS). These parameters were: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUV mean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor, of the pelvic nodes, of the paraaortic nodes and the metabolic volume of the metastases if any. RESULTS: A total of 38 patients with ACC fulfilled the inclusion criteria. All of them underwent a 18F-FDG PET/CT before definitive chemoradiotherapy. In the univariate analyses higher tumor size, pelvic lymph node metastasis and both MTV and TLG showed a significant association with OS and with RFS (MTV HR=1.55, p=0.011 and TLG HR=1.43, p=0.017 for RFS and MTV HR=1.82, p=0.006 and TLG HR=1.67, p=0.007 for OS). CONCLUSION: Pretreatment TLG sum and MTV sum seem to be independent prognostic factors for OS and RFS in patients with advanced cervical cancer treated with definitive chemoradiotherapy and they are better than the classic measurement of SUVmax.
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Glicólise/fisiologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluordesoxiglucose F18 , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Prognóstico , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Taxa de Sobrevida , Carga Tumoral , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/mortalidadeRESUMO
INTRODUCTION: Plantar fasciitis (PF) is one of the most frequent causes of thalalgia and disability. The effectiveness of extracorporeal shock wave therapy is an ideal alternative to conservative treatments. OBJETIVE: To evaluate the effectiveness of the treatment with Piezoelectric Focal Shock Waves with echographic support and maintenance of the effect at 3 and 6 months. MATERIALS AND METHODS: Causi-experimental, retrospective statistical study,June 2015 to June 2017, of 90 patients, 36.6% men and 63.3% women, with a mean age of 52 years, diagnosed with PF. Three sessions (one weekly for 3 weeks) of shock wave therapy (PiezoWave F10 G4 generator) were performed, with echographic support and weekly revision and at 3 and 6 months. MAIN VARIABLES: pain,using Visual Analog Scale before and after each session and at 3 and 6 months and Roles and Maudsley Scale at the end of treatment and at 3 and 6 months. RESULTS: 2000 pulses per session were applied, medium energy intensity 0.45 mJ /mm2, median frequency 8 MHz and median depth of focus of 15 mm. Statistically significant improvement was observed in the Visual Analog Scale between the 3 treatment sessions and after 3 and 6 months posttreatment,obtaining a statistically significant improvement in all values (p <0.05). CONCLUSION: Treatment with piezoelectric focal shock waves in PF may reduces pain from the first session and achieves a subjective perception of improvement, maintaining these results at 6 months post -treatment.
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Fasciíte Plantar/cirurgia , Procedimentos Cirúrgicos Ultrassônicos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor , Medição da Dor , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Background and objective Pneumonia remains the main cause of mortality in patients with systemic lupus erythematosus (SLE). The aim of the study was to establish the clinical characteristics, microbiology and risk factors for poor prognosis in patients with SLE and pneumonia. Methods We reviewed medical records of patients with SLE (American College of Rheumatology criteria) and pneumonia who attended the emergency room in a single tertiary care center (January 2010-March 2015). We collected demographics, treatment and disease activity (SLEDAI-2K) data. Severity scales of pneumonia (CURB-65 (acronym for risk factors measured: confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older) and Pneumonia Severity Index (PSI)) were obtained. A negative composite outcome was defined as need for mechanical ventilation, septic shock or death secondary to pneumonia up to 30 days after discharge. We conducted a univariate and multivariable analysis. Results We studied 158 patients (76% women) with 187 episodes of pneumonia. There were no differences in age, SLE duration, SLE activity, treatment or comorbidities between patients with negative composite outcome vs the other group. In 53 episodes, patients presented with a negative composite outcome. Of these, 46 (24.6%) required intubation, 13 (7%) developed shock and 12 (6.4%) died. The most common bacteria isolated was S. aureus, and we observed a high percentage of nonhabitual microorganisms. Fifteen percent of patients who presented with a negative outcome had low values on CURB-65 and PSI scales. Conclusion Patients with SLE and pneumonia have a high risk of complications and present with a high percentage of nonhabitual microorganisms. Severity scales for pneumonia can misclassify as low risk SLE patients with poor prognosis.
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Lúpus Eritematoso Sistêmico/complicações , Pneumonia/mortalidade , Staphylococcus aureus/isolamento & purificação , Adulto , Serviço Hospitalar de Emergência , Feminino , Humanos , Modelos Logísticos , Lúpus Eritematoso Sistêmico/microbiologia , Masculino , México , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Centros de Atenção Terciária , Adulto JovemRESUMO
Objective The purpose of this study was to describe the clinical characteristics of acute transverse myelitis, including the time of their presentation, and to evaluate their effect on accrual damage in patients with systemic lupus erythematosus (SLE). Methods Patients with SLE who were hospitalized because of incident, noninfectious myelitis at our institute between January 1997 and December 2013 were identified. As a control group, we selected for each of the patients in the study group one SLE patient hospitalized at the closest date to the case due to other severe non-neuropsychiatric (NP) SLE manifestation, with no history of NP manifestations or noninfectious disease. Clinical characteristics, laboratory results, treatment, disease activity (SLEDAI-2K), and damage (SLICC/ACR-DI) were collected from medical charts at the index hospitalization and one year after hospitalization. Results Demographics and SLE characteristics, including age at SLE diagnosis and time since SLE diagnosis to hospitalization, were comparable in patients with myelitis and controls. At hospitalization, disease activity and cumulative damage were similar in both groups. Patients with myelitis received more aggressive treatment than controls. One year after hospitalization, two of the 15 patients who completed follow-up had symptom improvement without neurologic sequelae, and 13 of them had some improvement of symptoms with neurologic sequelae. Four patients died in the myelitis group, three of them of infectious diseases, and one of alveolar hemorrhage. No patient died because of myelopathy and in the control group no patient died, although three were lost during the follow-up. Disease activity and treatment did not differ between both groups. However, cumulative damage was higher among the patients with myelitis than controls (1.9 ± 0.9 vs 0.75 ± 0.9; p = 0.003). Conclusion Patients with myelitis have clinical characteristics similar to those observed in non-NP SLE and receive more aggressive treatment. Furthermore, myelitis is associated with a significant increase in accrual damage compared with severe non-NP manifestations.
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Encéfalo/diagnóstico por imagem , Vasculite Associada ao Lúpus do Sistema Nervoso Central/complicações , Vasculite Associada ao Lúpus do Sistema Nervoso Central/tratamento farmacológico , Mielite Transversa/diagnóstico por imagem , Mielite Transversa/tratamento farmacológico , Adulto , Líquido Cefalorraquidiano/virologia , Ciclofosfamida/uso terapêutico , Feminino , Hospitalização , Humanos , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , México , Fármacos Neuroprotetores/uso terapêutico , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVE: The purpose of this study was to assess the utility of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) in serum and cerebrospinal fluid (CSF) as a biomarker in neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Thirty three NPSLE patients were evaluated at hospitalization and six months later. As controls, five SLE patients with septic meningitis, 51 hospitalized SLE patients without a history of neuropsychiatric (NP) manifestations and without infections, 16 SLE patients without NP manifestations (surgical-SLE), four patients with primary neuropsychiatric disorders, and 25 patients with non-autoimmune diseases were also studied. Serum and CSF samples were drawn at hospitalization, except non-NPSLE patients, in whom only serum was studied, and six months later in 19 NPSLE and 27 non-NPSLE patients. Serum and CSF TWEAK levels were measured by ELISA; values are expressed in pg/mL. RESULTS: The mean ± SD age of NPSLE patients was 31 ± 13.1 years, which was similar across study groups (p = 0.54). TWEAK levels in serum were not different across the study groups. In CSF, TWEAK levels were higher in NPSLE, surgical-SLE and primary neuropsychiatric groups than in non-autoimmune patients: median (IQR) 159.2 (94.1-374.9), 172.3 (125.3-421.9), 371.3 (143-543) vs. 122.1 (76.1-212.4), respectively; all p < 0.05. Six months later, when the neuropsychiatric manifestations were clinically in remission, serum or CSF TWEAK did not vary from baseline in NPSLE patients. CONCLUSIONS: TWEAK levels are slightly elevated in CSF in SLE patients compared with non-autoimmune controls, irrespective of the presence of NP manifestations. TWEAK levels in serum and CSF do not seem to be a useful biomarker of CNS involvement in SLE.
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Lúpus Eritematoso Sistêmico/diagnóstico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Fatores de Necrose Tumoral/sangue , Fatores de Necrose Tumoral/líquido cefalorraquidiano , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Citocina TWEAK , Ensaio de Imunoadsorção Enzimática , Feminino , Hospitalização , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/líquido cefalorraquidiano , Lúpus Eritematoso Sistêmico/terapia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/líquido cefalorraquidiano , Vasculite Associada ao Lúpus do Sistema Nervoso Central/terapia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Adulto JovemRESUMO
Este artículo analiza, desde una postura crítica, la utilización de la craneoplastia de compresión con vendaje como método de limitación de tratamiento de soporte vital (LTSV). Con esta técnica activa, algunos autores han propuesto provocar la muerte encefálica, posibilitando la donación de órganos. Al contrastar este procedimiento con las recomendaciones del documento de consenso sobre el tratamiento al final de la vida del paciente crítico, elaborado por el grupo de bioética de la SEMICYUC, se comprueba que los medios y fines de esta técnica no encajan con las actuaciones propias de la LTSV, que se basan en la retirada de medios de soporte vital o en su no inicio, al considerar dichos medios desproporcionados o extraordinarios en algunos casos, evitando así la obstinación terapéutica. La definición de LTSV permite clarificar los límites en los que, de un modo éticamente correcto y consensuado, las actuaciones al final de la vida se circunscriben a los fines de la medicina, evitando la sospecha de que dichas actuaciones puedan ser malinterpretadas como justificación para una obtención de órganos abusiva. El artículo concluye que la provocación directa de la muerte encefálica mediante la técnica de craneoplastia con vendaje no parece cumplir los criterios propios de la LTSV.
This article analyzes, from a critical perspective, the use of cranioplasty with oppressive binder as a method to limit life support treatment (LLST). Some authors have proposed that this active technique provokes encephalic death, allowing organ donation. Contrasting this procedure with the recommendations of the consent document about treatment of critical patients at the end of life, elaborated by the bioethics group of SEMICYUC, it is shown that the means and ends of this technique do not match with the proper actions of LLST, based on the withdrawal of life support means or in not starting them, considering such means disproportionate or extraordinary in some cases, thus avoiding the therapeutic obstinacy. The definition of LLST allows to clarify the limits in which, in a way ethically fair and with a consensus, the acts at the end of life are included in the medical goals, avoiding the suspicion that these acts may be misinterpreted as justifying an abusive extraction of organs. This article concludes that the direct provocation of encephalic death by the technique of cranioplasty with binder does not appear to fulfill the criteria proper of LLST.
Este artigo analisa, a partir de uma postura crítica, a utilização da cranioplastia de compressão com curativo como método de limitação de tratamento de suporte vital (LTSV). Com esta técnica ativa, alguns autores têm proposto provocar a morte encefálica, possibilitando a doação de órgãos. Ao contrastar este procedimento com as recomendações do documento de consenso sobre o tratamento do final de vida do paciente crítico, elaborado pelo grupo de bioética da SEMICYUC, se comprova que os meios e fins desta técnica não encaixam com as atuações próprias da LTSV, que se baseiam na retirada de meios de suporte vital ou em seu não início, ao considerar os ditos meios desproporcionados ou extraordinários em alguns casos, evitando assim a obstinação terapêutica. A definição de LTSV permite esclarecer os limites nos quais, de um modo eticamente correto e aceito, as atuações ao final da vida se circunscrevem às finalidades da medicina, evitando a suspeita de que ditas atuações podem ser mal interpretadas como justificativa para uma obtenção de órgãos abusiva. O artigo conclui que a provocação direta da morte encefálica mediante a técnica da cranioplastia com curativo não parece cumprir os critérios próprios da LTSV.
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Humanos , Craniectomia Descompressiva/ética , Cuidados para Prolongar a Vida/ética , Obtenção de Tecidos e Órgãos/ética , Obtenção de Tecidos e Órgãos/métodos , Bandagens CompressivasAssuntos
Adenocarcinoma Mucinoso/terapia , Neoplasias do Apêndice/terapia , Complicações Neoplásicas na Gravidez/terapia , Adenocarcinoma Mucinoso/patologia , Adulto , Neoplasias do Apêndice/patologia , Apêndice/patologia , Feminino , Humanos , Gravidez , Complicações Neoplásicas na Gravidez/patologiaRESUMO
Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the salivary and lacrimal glands. The aim of the study was to characterize and compare the presence of diverse cytokines and regulatory T and B cells in lip minor salivary gland (MSG) biopsies from patients with primary Sjögren's syndrome (pSS), secondary SS (sSS), and patients with connective tissue disease (CTD) without (w/o) SS. We included samples of MSG from 15 pSS, 24 sSS (six scleroderma, nine rheumatoid arthritis and nine lupus patients) and 15 patients with CTD w/o SS. Tissues were examined by an indirect immunoperoxidase technique (goat polyclonal anti-human IL-19, goat polyclonal anti-human IL-22 or mouse monoclonal anti-human IL-24). To determine the subpopulation of CD4(+)/IL-17A(+)-, CD4(+)/IL-4(+)-, CD4(+)/IFN-É£(+)-expressing T cells, CD25(+)/Foxp3(+) Treg cells and CD20(+)/IL-10(+)-producing B cell subset, a double-staining procedure was performed. We estimated the mean percentage of positively staining cells in two fields per sample. CD4(+)/IFN-É£(+), CD4(+)/IL-4(+) and IL-22(+) cell percentages were elevated in both SS varieties; however, the cells were more prevalent in pSS. Patients with pSS had a high number of CD4(+)/IL-17A(+) and IL-19(+) T cells and a lower percentage of IL-24(+) cells (P < 0.05). The Treg and IL-10-producing B cells were increased in pSS (P < 0.05). Concluding, in our patients, a pro-inflammatory and regulatory balance coexists in SS, being both responses more intense in pSS. The explanation of these differences may be related to disease activity, disease duration and treatment.
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Linfócitos B Reguladores/imunologia , Linfócitos B Reguladores/metabolismo , Citocinas/metabolismo , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto , Antígenos de Superfície/metabolismo , Biomarcadores/metabolismo , Biópsia , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Glândulas Salivares Menores/imunologia , Glândulas Salivares Menores/metabolismo , Glândulas Salivares Menores/patologia , Síndrome de Sjogren/patologiaRESUMO
BACKGROUND: Alterations in the NOTCH1 signaling pathway are found in about 60% of pediatric T-ALL, but its impact on prognosis remains unclear. PROCEDURE: We extended the previously published CoALL cohort (n = 74) to a larger cohort (n = 127) and additionally included 38 Argentine patients from ALL IC-BFM to potentially identify novel mutations and decipher a stronger discriminatory effect on the genotype/phenotype relationship with regard to early treatment response and long-term outcome. RESULTS: Overall, 101 out of 165 (61.2%) T-ALL samples revealed at least one NOTCH1 mutation, 28 of whom had combined NOTCH1 and FBXW7 mutations. Eight T-ALL samples (4.8%) exclusively revealed FBXW7 mutations. Fifty-six T-ALL (33.9%) exhibited a wild-type configuration of either gene. Four novel NOTCH1 mutations were identified localized in the C-terminal PEST domain, in the rarely affected LNR repeat domain and in the ankyrin domain. Novel LNR mutations may contribute to a better understanding of the structure of the NOTCH1 negative regulatory region (NRR) and the R1946 mutation in the ankyrin domain may represent an unusual loss-of-function mutation. CONCLUSIONS: Overall, NOTCH1 pathway mutations did not affect the relapse rate and outcome of the extended T-ALL cohort uniformly treated according to CoALL protocols, although NOTCH1 mutations were associated with good response to induction therapy (P = 0.009). Individually, HD and PEST domain mutations might exert distinct functional effects on cellular homeostasis under treatment NOTCH1 pathway activity with prognostic implications.
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Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Mutação/genética , Recidiva Local de Neoplasia/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética , Ubiquitina-Proteína Ligases/genética , Criança , Estudos de Coortes , DNA de Neoplasias/genética , Proteína 7 com Repetições F-Box-WD , Genótipo , Humanos , Recidiva Local de Neoplasia/terapia , Fenótipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Taxa de SobrevidaRESUMO
BACKGROUND: Localized scleroderma (LS) is a disfiguring inflammatory autoimmune disease of the skin and underlying tissue. As in systemic sclerosis, a key feature is the presence of T cells in inflammatory lesions. AIM: To evaluate the effect of polymerized type I collagen vs. methylprednisolone (MP) in LS, and to determine the influence of this polymerized collagen (PC) on CD4+ peripheral T cells expressing interleukin (IL)-4, IL-17A, interferon-γ and Forkhead box protein (Foxp)3, and on cells expressing transforming growth factor (TGF)-ß1, IL-17A, IL-22 and Foxp3 in the skin. METHODS: In total, 16 patients with LS were treated for 3 months with monthly subcutaneous intralesional injections of 0.1 mL MP (giving a total dose of 20 mg/mL each month) and 15 patients were treated, with weekly subcutaneous intralesional injections of PC, ranging from 0.2 mL (equivalent to 1.66 mg collagen) for a lesion of 50 mm in size, up to a maximum of 1.0 mL (8.3 mg collagen) for a lesion > 100 mm in size, and followed up for a further 6 months. Skin biopsies were obtained from lesions at baseline (before treatment) and 9 months later (6 months after treatment end). Tissue sections were evaluated by histology and immunohistochemistry (IL-17A, IL-22, TGF-ß1 and Foxp3). CD4+ T-cell subsets were determined in peripheral blood by flow cytometry. RESULTS: Abnormal tissue architecture was seen in the biopsies taken from patients treated with MP, whereas the PC treatment restored normal skin architecture. PC downregulated pro-inflammatory/profibrotic cytokine expression in peripheral cells, and upregulated the number of regulatory T cells (Tregs) in skin. PC was safe and well tolerated. CONCLUSIONS: PC is not only an antifibrotic/fibrolytic agent but also an immunomodulator biodrug that restores the balance between T helper (Th)1, Th2, Th17 and Tregs, downregulates production of pro-inflammatory or profibrogenic cytokines (IL-17A, IL-22 and TGF-ß1), and renews skin architecture, without adverse effects.
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Colágeno Tipo II/administração & dosagem , Fatores de Transcrição Forkhead/metabolismo , Interleucina-17/metabolismo , Interleucinas/metabolismo , Esclerodermia Localizada/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Adolescente , Adulto , Idoso , Colágeno Tipo II/farmacologia , Método Duplo-Cego , Regulação para Baixo , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Esclerodermia Localizada/metabolismo , Esclerodermia Localizada/patologia , Linfócitos T/metabolismo , Adulto Jovem , Interleucina 22RESUMO
Renal allograft survival is related directly to cell senescence. In the transplantation scenario many cellular events - participating as immunological and non-immunological factors - could contribute to accelerate this biological process, responsible for the ultimate fate of the graft. Mechanisms concerned in tolerance versus rejection are paramount in this outcome. For this reason, immunosuppressive treatment constitutes an extremely important decision to prevent organ dysfunction and, finally, graft loss. This study was conducted to document the proportion of CD4(+) /interleukin (IL)-17A(+) -, CD16(+) /indoleamine 2, 3-dioxygenase (IDO(+) )-, forkhead box protein P3 (FoxP3(+))-expressing cells, senescent cells (p16(INK) (4α)) and the percentage of interstitial fibrosis (IF) in graft biopsies of kidney transplant recipients participating in the BENEFIT (Bristol-Myers Squibb IM103008) study. CD4(+) /IL-17A(+) , CD16(+) /IDO(+), FoxP3(+) and p16(INK) (4α+) cells were evaluated by immunohistochemistry, and the percentage of IF by morphometry on graft biopsies obtained at time 0 (pre-implantation) and at 12 months post-transplant. Senescent cells and CD4(+) /IL-17A(+) cells were increased among graft biopsies in subjects receiving cyclosporin A (CsA) compared to those under belatacept treatment. Meanwhile, CD16(+) /IDO(+) and FoxP3(+) -expressing cells were lower in biopsies from CsA treatment compared to patients treated with Belatacept. Histological morphometric analyses disclosed more IF in 12-month CsA-treated patients in comparison to pre-implantation biopsy findings. Summing up, renal biopsies from patients receiving belatacept showed greater amounts of FoxP3(+) cells and lower amounts of CD4(+) /IL-17A(+) and senescent cells compared to patients under CsA treatment. Along with these findings, an increase in IF in annual CsA-treated-patients biopsies compared to pre-implantation and belatacept-treated patients were observed.
Assuntos
Senescência Celular/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Ciclosporina/farmacologia , Regulação para Baixo/efeitos dos fármacos , Fatores de Transcrição Forkhead/biossíntese , Imunoconjugados/farmacologia , Imunossupressores/farmacologia , Transplante de Rim , Rim/patologia , Nefrite Intersticial/induzido quimicamente , Abatacepte , Corticosteroides/uso terapêutico , Adulto , Anticorpos Monoclonais/uso terapêutico , Basiliximab , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Ciclosporina/uso terapêutico , Método Duplo-Cego , Feminino , Fatores de Transcrição Forkhead/genética , Genes p16 , Humanos , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Nefrite Intersticial/imunologia , Nefrite Intersticial/metabolismo , Nefrite Intersticial/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
The thyroid hormone receptor (TR) is a suppressor of ras-mediated responses. To characterize the receptor domains involved in this function, we analyzed a panel of TRß1 mutants for their ability to interfere with ras-driven cyclin D1 activation, formation of transformation foci and tumor growth in nude mice. Our results show that the domains and mechanisms responsible for the anti-transforming and anti-tumorigenic actions of the receptor are divergent from those operating in classical T3-dependent transcriptional activation. TRß1 mutants that do not bind coactivators and do not transactivate retained the capacity of suppressing cellular transformation and tumor growth, whereas selective mutations in the hinge region affecting corepressors recruitment abolished these actions, while preserving ligand-dependent transcription. There was a strict parallelism between anti-transforming activity of the various mutants and their ability to antagonize cyclin D1 stimulation by ras, indicating that transrepression mechanisms may have an important function in suppression of the transforming effects of the oncogene by TRß1. The inhibitory action of T3 on transformation was further enhanced after over-expression of corepressors, while corepressor depletion by means of small-interference RNA reversed significantly hormonal action. This shows an important functional role of endogenous corepressors in suppression of ras-mediated transformation and tumorigenesis by TRß1.
Assuntos
Transformação Celular Neoplásica/genética , Proteínas Correpressoras/metabolismo , Genes ras , Domínios e Motivos de Interação entre Proteínas , Receptores beta dos Hormônios Tireóideos/metabolismo , Animais , Proteínas Correpressoras/genética , Ciclina D1/metabolismo , Células Hep G2 , Humanos , Camundongos , Camundongos Nus , Mutação , RNA Interferente Pequeno/metabolismo , Receptores beta dos Hormônios Tireóideos/genética , Tri-Iodotironina/metabolismoRESUMO
BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme that suppresses T-lymphocyte activity. Costimulation blockade through CTLA4lg increases IDO in antigen-presenting cells. The suppressive effect of IDO is thought to be mediated by Foxp3+CD4+CD25+ regulatory T-cells (Tregs). OBJECTIVE: In this descriptive study, we evaluated the percentage of IDO-expressing peripheral cell subpopulations as well as Tregs in 27 stable kidney transplant recipients receiving either belatacept (LEA29Y), a daughter compound of abatacept (CTLA4lg; n = 19) or cyclosporine (n = 8). METHODS: Blood samples were obtained at 24 ± 2 months (belatacept) and 23 ± 6 months (cyclosporine) of treatment. Intracellular IDO was analyzed by flow cytometry in CD14+, CD11c+, CD16+, CD56+, and CD8+ cell subpopulations. Tregs were assessed by intracellular Foxp3 detection in CD4+CD25+ cells. CD3+, CD4+, CD8+, CD20+, CD68+, IDO+, and Foxp3+ cells were evaluated by immunohistochemistry on graft biopsies obtained preimplantation, at 12 months posttransplant, and in subjects with dysfunction during the first 12 months. RESULTS: Only percentages of CD16+/IDO+-expressing peripheral monocytes were significantly increased among the group receiving belatacept. No differences were observed in peripheral Tregs between the groups. In contrast, higher percentages of Tregs, CD4+, CD8+, and CD68+ cells were noted in dysfunction and at 12 months vs baseline among graft biopsies in subjects receiving belatacept, and also among dysfunction cohorts of belatacept vs Cyclosporine treatment. CONCLUSION: Patients receiving belatacept showed greater amounts of peripheral blood CD16+/IDO+ cells and Tregs on graft biopsies than those under cyclosporine treatment.
Assuntos
Células Apresentadoras de Antígenos/efeitos dos fármacos , Ciclosporina/administração & dosagem , Imunoconjugados/administração & dosagem , Imunossupressores/administração & dosagem , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Transplante de Rim , Rim/efeitos dos fármacos , Receptores de IgG/sangue , Linfócitos T Reguladores/efeitos dos fármacos , Abatacepte , Adulto , Células Apresentadoras de Antígenos/enzimologia , Células Apresentadoras de Antígenos/imunologia , Biópsia , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Proteínas Ligadas por GPI/sangue , Humanos , Imuno-Histoquímica , Rim/imunologia , Rim/patologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Histone deacetylases (HDACs) remove the acetyl groups of lysine residues of histone tails leading to chromatin compaction and transcriptional repression. In addition, HDACs can also influence transcription-independent events such as mitosis or deoxyribonucleic acid (DNA) repair and deacetylate nonhistone proteins involved in cell proliferation and death, altering their function. Histone deacetylase inhibitors (HDACi) constitute a promising treatment for cancer therapy due to their low toxicity. HDACi have been shown to induce differentiation, cell-cycle arrest, and apoptosis and to inhibit migration, invasion, and angiogenesis in many cancer cell lines. In addition, these compounds inhibit tumor growth in animal models and show antitumor activity in patients. HDACi alone and in combination with a variety of anticancer drugs are being tested in clinical trials, showing significant anticancer activity both in hematological and solid tumors. SAHA (vorinostat, Zolinza) was the first HDACi approved by the US Food and Drug Administration to enter the clinical oncology market for treating cutaneous T-cell lymphoma (CTCL) and is being tested for other malignancies.