A Fashi Lymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation.

Human T-cell lymphotropic virus (HTLV)-1 was the first human retrovirus to be associated to cancer, namely adult T-cell leukemia (ATL), but its pathogenesis remains enigmatic, since only a minority of infected individuals develops either ATL or the neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A functional FAS -670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL and HAM/TSP susceptibility. Fashi T stem cell memory (Tscm) cells have been identified as the hierarchical apex of ATL, but have not been investigated in HAM/TSP. In addition, both FAS and STAT1 have been identified in an IFN-inducible HAM/TSP gene signature, but its pathobiological significance remains unclear. We comprehensively explored Fas expression (protein/mRNA) and function in lymphocyte activation, apoptosis, proliferation, and transcriptome, in PBMC from a total of 47 HAM/TSP patients, 40 asymptomatic HTLV-1-infected individuals (AC), and 58 HTLV-1 -uninfected healthy controls. Fas surface expression followed a two-step increase from HC to AC and from AC to HAM/TSP. In HAM/TSP, Fas levels correlated positively to lymphocyte activation markers, but negatively to age of onset, linking Fashi cells to earlier, more aggressive disease. Surprisingly, increased lymphocyte Fas expression in HAM/TSP was linked to decreased apoptosis and increased lymphoproliferation upon in vitro culture, but not to proviral load. This Fashi phenotype is HAM/TSP-specific, since both ex vivo and in vitro Fas expression was increased as compared to multiple sclerosis (MS), another neuroinflammatory disorder. To elucidate the molecular mechanism underlying non-apoptotic Fas signaling in HAM/TSP, we combined transcriptome analysis with functional assays, i.e., blocking vs. triggering Fas receptor in vitro with antagonist and agonist-, anti-Fas mAb, respectively. Treatment with agonist anti-Fas mAb restored apoptosis, indicating biased, but not defective Fas signaling in HAM/TSP. In silico analysis revealed biased Fas signaling toward proliferation and inflammation, driven by RelA/NF-κB. Correlation of Fas transcript levels with proliferation (but not apoptosis) was confirmed in HAM/TSP ex vivo transcriptomes. In conclusion, we demonstrated a two-step increase in Fas expression, revealing a unique Fashi lymphocyte phenotype in HAM/TSP, distinguishable from MS. Non-apoptotic Fas signaling might fuel HAM/TSP pathogenesis, through increased lymphoproliferation, inflammation, and early age of onset.

Immunological Profile in Individuals with Schistosomal Myeloradiculopathy.

BACKGROUND: Schistosomal myeloradiculopathy (SMR) is the most serious ectopic presentation of Schistosoma mansoni infection. The pathogenesis occurs mainly via the host inflammatory response to the eggs of the parasite that are stuck in the central nervous system, and the diagnosis is generally made by the exclusion of other neurological diseases. OBJECTIVE: We aimed to evaluate the immune status of SMR patients and to identify a marker for SMR diagnosis. METHODS: We enrolled 15 patients with a presumptive diagnosis of SMR, and the control groups included 17 patients with myelopathy associated with human T cell lymphotropic virus type 1 (HTLV-1) and 11 with other neurological disorders. The determination of soluble egg antigen-specific IgE and the levels of cytokines from Th1, Th2, Th17 and T-regulatory cell profiles and the chemokines MIP-1a and RANTES were measured in the cerebrospinal fluid (CSF) and serum using an ELISA technique. RESULTS: We observed that SMR leads to an increase in IgE levels in the CSF compared to serum, and the levels of IL-13 and MIP-1α were significantly higher in the CSF and serum of the SMR patients than in the patients with HTLV-1-associated myelopathy. The levels of MIP-1α and RANTES were higher in the CSF than in the serum of the SMR group. The ratio between levels of IL-13, MIP-1α and RANTES over IL-10 was positive in the CSF of the SMR patients. CONCLUSIONS: These results indicate that S. mansoni-specific IgE in the CSF is a promising marker for the diagnosis of SMR and that the cytokines and chemokines associated with the Th2 profile may be important factors in the immunopathogenesis of SMR.

Pilates exercises improve low back pain and quality of life in patients with HTLV-1 virus: a randomized crossover clinical trial.

BACKGROUND: Low back pain is highly prevalent in patients with HTLV-1. The effects of physical activity on this condition are not known, but postural misalignment and motor deficits are frequently present. OBJECTIVES: To assess the effect of Pilates exercises on chronic low back pain in these patients, and its impact on quality of life. METHODS: A randomized crossover clinical trial was conducted, involving 22 patients from a reference center in Salvador, Bahia, Brazil. The VAS was used to evaluate the effect of Pilates on pain intensity and the SF-36 to assess its impact on quality of life. RESULTS: Our results provide evidence of positive effects on pain intensity and almost all domains of quality of life when patients followed the Pilates exercise program described. CONCLUSION: The Pilates method may be a useful tool in alleviating the symptoms of low back pain, and had a significant impact on quality of life in this sample of patients.

Epidemiology of the amyotrophic lateral sclerosis Bahia: Brazil

The Amyotrophic Lateral Sclerosis is a neurological disorder, with the degeneration of the upper and lower motor neurons. The aim is investigate the start of the symptoms, describe the findings and study the survival period of patients with ALS. We analyzed 70 patients. The patients’ average age was 49.68 years old and we found 43 patients (61.4 percent) who were white, 22 who were grayish brown (31.4 percent) and 5 who were black (7.1 percent). Regarding the start of the symptoms, 51 patients (72.9 percent) showed a distal start, 31 a proximal one (44.3 percent) and 8 of them (11.4 percent) showed a bulbar start. The survival period, after de diagnosis, was of 64.11 months. The mean age, signs and symptoms and the patients’ survival period we found, are compatible with the ones found in the literature, except for the number of black patients, that was bigger in our survey.

A esclerose lateral amiotrófica (ELA) é uma desordem neurológica com degeneração dos neurônios motores superiores e inferiores. Objetivo: investigar o inicio dos sintomas, descrever a evolução e os achados neurológicos e estudar a sobrevida dos pacientes com ELA. Método: Analisamos 70 pacientes entre 1996 e 2007, que preencheram os critérios propostos no El Escorial, sendo 52 do sexo masculino e 18 do sexo feminino. A média de idade dos pacientes era de 49,6857 anos, encontramos 43 (61,4 por cento) brancos, 22 (31,4 por cento) pardos e 5 (7,1 por cento) negros. Quanto ao inicio dos sintomas, 51 (72,9 por cento) dos pacientes apresentaram inicio distal, 31 (44,3 por cento) de forma proximal e 8 (11,4 por cento) de forma bulbar. Os sintomas mais comuns foram dos fraqueza muscular, atrofia muscular e miofasciculações presente em 69 (98,6 por cento) pacientes. A sobrevida após diagnóstico foi de 64,116 meses. Conclusão: A idade média, os sinais e sintomas e a sobrevida dos pacientes analisados são compatíveis com os encontrados na literatura, exceto pela quantidade de pacientes da raça negra, que foi maior.

Evolution of HTLV-1 proviral load in patients from Salvador, Brazil.

INTRODUCTION: Variations in human T cell lymphotropic virus type 1 (HTLV-1) proviral load (PVL) in infected individuals over time are not well understood. OBJECTIVE: To evaluate the evolution of proviral load in asymptomatic individuals and HAM/TSP patients in order to help determine periodicity for measuring proviral load. METHODS: A group of 104 HTLV-1 infected patients, followed at the HTLV reference center in Salvador, Brazil, were included in the study (70 asymptomatic and 34 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients). HTLV-1 PVL was measured using real-time polymerase chain reaction (PCR) at baseline and again at another point, either ≤ 12 months, between 12-24 months, or ≥ 24 months. RESULTS: HAM/TSP patients had higher PVL (ranging from 11,041 to 317,009 copies/10(6) PBMC) when compared to asymptomatic individuals (ranging from 0 to 68,228 copies/10(6) PBMC). No statistically significant differences were observed in the medians of PVL in HAM/TSP patients or asymptomatic individuals over time. However, in asymptomatic individuals with a PVL below 50,000 copies/10(6) PBMC, a statistically significant two-fold increase was observed over time. CONCLUSION: HTLV-1-PVL remained stable in both asymptomatic individuals and HAM/TSP patients over time. Frequent monitoring of asymptomatic individuals with low PVLs is recommended and further studies should be conducted to assess the course of PVL in these patients over extended periods of time.

Ascorbic acid has superior ex vivo antiproliferative, cell death-inducing and immunomodulatory effects over IFN-α in HTLV-1-associated myelopathy.

BACKGROUND: Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA) monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP. PRINCIPAL FINDINGS: Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes. CONCLUSIONS: In comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.

Evolution of HTLV-1 proviral load in patients from Salvador, Brazil

INTRODUCTION: Variations in human T cell lymphotropic virus type 1 (HTLV-1) proviral load (PVL) in infected individuals over time are not well understood. Objective: To evaluate the evolution of proviral load in asymptomatic individuals and HAM/TSP patients in order to help determine periodicity for measuring proviral load. METHODS: A group of 104 HTLV-1 infected patients, followed at the HTLV reference center in Salvador, Brazil, were included in the study (70 asymptomatic and 34 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients). HTLV-1 PVL was measured using real-time polymerase chain reaction (PCR) at baseline and again at another point, either < 12 months, between 12-24 months, or > 24 months. RESULTS: HAM/TSP patients had higher PVL (ranging from 11,041 to 317,009 copies/10(6) PBMC) when compared to asymptomatic individuals (ranging from 0 to 68,228 copies/10(6) PBMC). No statistically significant differences were observed in the medians of PVL in HAM/TSP patients or asymptomatic individuals over time. However, in asymptomatic individuals with a PVL below 50,000 copies/10(6) PBMC, a statistically significant two-fold increase was observed over time. CONCLUSION: HTLV-1-PVL remained stable in both asymptomatic individuals and HAM/TSP patients over time. Frequent monitoring of asymptomatic individuals with low PVLs is recommended and further studies should be conducted to assess the course of PVL in these patients over extended periods of time.

Comparison between the spastic paraplegia rating scale, Kurtzke scale, and Osame scale in the tropical spastic paraparesis/myelopathy associated with HTLV / Comparação entre a escala para paraplegia espástica, escala de Kurtzke e escala de Osame, na paraparesia epástica tropical/mielopatia associada ao HTLV

INTRODUCTION:The objective of this study was to compare Osame's scale of motor incapacity and the expanded scale of the state of incapacity of Kurtzke with the spastic paraplegia rating scale for the clinical evaluation of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). METHODS: Patients with the diagnosis of infection by HTLV-I/HTLV-II and with the clinical suspicion of HAM/TSP were included in the study. RESULTS: There were 45 patients who were evaluated. When analyzing the results of the scales, the researchers found the following averages of 21.08 points for the spastic paraplegia rating scale, 4.35 points for Osame's scale, and 4.77 points for Kurtzke's scale. The relation between the scale of paraplegia with Osame's was very significant with p < 0.0001, and regarding Kurtzke's scale, there was a similar result of p < 0.0001. When comparing Osame's, Kurtze's, and the spastic paraplegia rating scale with the time of disease, the researchers found a significant result of p = 0.0004 for the scale of spastic paraplegia, p = 0.0018 for Osame's scale, and p < 0.0001 for Kurtzke's scale. CONCLUSION: The spastic paraplegia rating scale has a good relation with Osame's and Kurtzke's scales showing a p index that is very significant that indicates that, although the scale was not initially made to be applied to patients with HAM/TSP because of the infection by HLTV, it showed to be as efficient as Osame's and Kurtzke's scales in evaluating the patients' neurological conditions.

INTRODUÇÃO:O objetivo deste estudo foi comparar a escala de incapacidade motora de Osame e a escala expandida do estado de incapacidade de Kurtzke com a escala para avaliação da paraplegia espástica com o objetivo de avaliar a clinica dos pacientes com mielopatia associada a HTLV-I/paraparesia espastica tropical (PET/MAH). MÉTODOS: Foram incluídos pacientes com diagnóstico de infecção pelo HTLV-I/HTLV-II e a suspeita clinica de PET/MAH. RESULTADOS: Foram avaliados 45 pacientes. Ao analisar os resultados das escalas encontramos as seguintes médias de 21,08 pontos para a escala para paraplegia espástica, 4,35 pontos para a escala de Osame e 4,77 pontos para a de Kurtze. A relação entre a escala de paraplegia com a de Osame foi muito significativa com p < 0.0001, e com relação a escala de Kurtze obteve resultado semelhante com p < 0.0001, também significante. Comparando-se as escalas de Osame, Kurztze e escala para avaliação da paraplegia espástica com o tempo de doença obtivemos um resultado significante com p=0,0004, para a escala de paraplegia espastica, p = 0,0018 para a escala de Osame e p < 0,0001 para a escala de Kurtzke. CONCLUSÕES: A escala da paraplegia espástica possui boa relação com as escalas de Osame e Kurzte, mostrando um p muito significativo, indicando que apesar da escala não ter sido feita inicialmente para ser aplicada aos pacientes com PET/MAH devido à infecção pelo HLTV, ela se mostrou capaz de ser tão eficiente quanto às escalas de Osame e Kurtzke para avaliar o quadro neurológico dos pacientes.

Impact of depression on quality of life in people living with human T cell lymphotropic virus type 1 (HTLV-1) in Salvador, Brazil.

PURPOSE: A previous study found the prevalence of depression in HTLV-1-infected patients to be approximately 30%, but few studies have attempted to correlate depression with quality of life (QOL) in these patients. The present study investigates the association between depression and QOL in people living with HTLV-1. METHODS: A clinical-epidemiological questionnaire, the Mini International Neuropsychiatric Interview and the WHOQOL-Bref were applied to 88 HTLV-1-infected patients (32 with TSP/HAM) at the HTLV Center of the Bahiana School of Medicine and Public Health, Salvador, Brazil. RESULTS: The prevalence of depression among people living with HTLV-1 was 34.1%. Depression was significantly associated with a poor QOL in the physical, psychological, social relationship and environment domains, when controlling for other variables, such as gender, age, time of knowledge of serological diagnosis and presence of tropical spastic paraparesis/HTLV-1associated myelopathy (TSP/HAM). Moreover, patients with TSP/HAM experienced a reduction in their QOL in the physical, psychological and environment domains. CONCLUSION: Our results showed that depression negatively affects the quality of life of people living with HTLV-1, regardless of the presence of TSP/HAM. Since it is possible to improve a patient's QOL by treating depression, psychological evaluations are strongly recommended as a measure to integrate the treatment protocols of HTLV-1 intervention programs.

Keratoconjunctivitis sicca of human T cell lymphotropic virus type 1 (HTLV-1) infected individuals is associated with high levels of HTLV-1 proviral load.

BACKGROUND: A high HTLV-1 proviral load is found in HTLV-1-associated diseases, mainly HAM/TSP. However, the association between proviral load and keratoconjunctivitis sicca (KCS) has not been well established. AIM: To verify the association between KCS and HTLV-1 proviral load. STUDY DESIGN: 104 HTLV-1 infected patients (51 asymptomatic and 52 with HAM/TSP) from the HTLV reference center in Salvador, Brazil were followed from June 2008 to May 2010. Evaluation of tear secretion was performed by BUT (break-up time), Rose Bengal and Schirmer I tests. The diagnosis of KCS was based upon the presence of symptoms and when at least two of three tests were positive. HTLV-1 proviral load was determined using real-time PCR. RESULTS: The prevalence of KCS was 44.2%. KCS was more frequent among HAM/TSP patients (p = 0.022). Patients with KCS had higher proviral load (mean 134,672 ± 150,393copies/10(6) PBMC) than patients without the disease (mean 66,880 ± 109,525copies/10(6) PBMC) (p = 0.001). HTLV-1 proviral load>100,000copies/10(6) PBMC increased significantly the risk of developing KCS (OR = 4.05 and 95% CI = 1.40-11.76). After age>45 years and HAM/TSP status were excluded in stepway reward analysis, the variables PVL>100,000 (OR = 4.77 and 95% CI = 1.83-12.44) still remained statistically significant. CONCLUSION: HTLV-1 proviral loads are higher in patients with KCS and may represent a relevant biological marker of disease.

Human T cell lymphotropic virus type 1 (HTLV-1) proviral load of HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients according to new diagnostic criteria of HAM/TSP.

A high human T-cell lymphotropic virus type 1 (HTLV-1) proviral load is described in HTLV-1-associated diseases, especially HAM/TSP. However, the cut-off value to define high levels of HTLV-1 proviral load is not well established. 281 HTLV-1-infected patients from the HTLV reference center in Salvador, Brazil, were followed from 2005 to 2008. Patients were classified as asymptomatic, possible-, probable-, and definite-HAM/TSP, in accordance with diagnostic criteria proposed by De Castro-Costa et al. (2006): AIDS Res Hum Retroviruses 22:931-935. HTLV-1 proviral load was determined using real-time PCR. A receiver operator characteristic (ROC) curve was constructed using only asymptomatic individuals and definite-HAM/TSP patients. The ROC curve was used to predict the proviral load level that differentiates these two groups. Out of 281 patients, 189 were asymptomatic and 92 were diagnosed with HAM/TSP (22 possible, 23 probable, 47 definite). The mean HTLV-1 proviral load was higher in possible- (89,104 ± 93,006 copies/106 PBMC), -probable (175,854 ± 128,083 copies/106 PBMC), and definite-HAM/TSP patients (150,667 ± 122,320 copies/106 PBMC),when compared to asymptomatic individuals (27,178 ± 41,155 copies/106 PBMC) (P < 0.0001). A comparison of all HAM/TSP groups showed the highest proviral loads in probable-HAM/TSP patients, yet the differences in mean values were not statistically significant. The ROC curve suggested a value of 49,865 copies/106 PBMC, with 87% sensitivity (95% CI » 74-95) and 81% specificity (95% CI » 75-86), as the best proviral load cut-off point to differentiate definite HAM/TSP patients from asymptomatic individuals. HTLV-1 proviral loads are higher in groups of infected patients with eurological symptoms and may represent a relevant biological marker of disease progression.