Tropical Spastic Paraparesis Research Articles

A novel positive feedback-loop between the HTLV-1 oncoprotein Tax and NF-\u03baB activity in T-cells

BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) infects primarily CD4+ T-lymphocytes and evoques severe diseases, predominantly Adult T-Cell Leukemia/ Lymphoma (ATL/L) and HTLV-1-associated Myelopathy/ Tropical Spastic Paraparesis (HAM/TSP). The viral transactivator of the pX region (Tax) is important for initiating malignant transformation, and deregulation of the major signaling pathway nuclear factor of kappa B (NF-κB) by Tax represents a hallmark of HTLV-1 driven cancer.ResultsHere we found that Tax mutants which are defective in NF-κB signaling showed diminished protein expression levels compared to Tax wildtype in T-cells, whereas Tax transcript levels were comparable. Strikingly, constant activation of NF-κB signaling by the constitutive active mutant of inhibitor of kappa B kinase (IKK2, IKK-β), IKK2-EE, rescued protein expression of the NF-κB defective Tax mutants M22 and K1-10R and even increased protein levels of Tax wildtype in various T-cell lines while Tax transcript levels were only slightly affected. Using several Tax expression constructs, an increase of Tax protein occurred independent of Tax transcripts and independent of the promoter used. Further, Tax and M22 protein expression were strongly enhanced by 12-O-Tetradecanoylphorbol-13-Acetate [TPA; Phorbol 12-myristate 13-acetate (PMA)]/ ionomycin, inducers of NF-κB and cytokine signaling, but not by tumor necrosis factor alpha (TNF-α). On the other hand, co-expression of Tax with a dominant negative inhibitor of κB, IκBα-DN, or specific inhibition of IKK2 by the compound ACHP, led to a vast decrease in Tax protein levels to some extent independent of Tax transcripts in transiently transfected and Tax-transformed T-cells. Cycloheximide chase experiments revealed that co-expression of IKK2-EE prolongs the half-life of M22, and constant repression of NF-κB signaling by IκBα-DN strongly reduces protein stability of Tax wildtype suggesting that NF-κB activity is required for Tax protein stability. Finally, protein expression of Tax and M22 could be recovered by NH4Cl and PYR-41, inhibitors of the lysosome and the ubiquitin-activating enzyme E1, respectively.ConclusionsTogether, these findings suggest that Tax’s capability to induce NF-κB is critical for protein expression and stabilization of Tax itself. Overall, identification of this novel positive feedback loop between Tax and NF-κB in T-cells improves our understanding of Tax-driven transformation.

HLA-B*35 as a new marker for susceptibility to human T-cell lymphotropic virus type 1 (HTLV-1) Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in patients living in Argentina

BackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV associated myelopathy/ Tropical Spastic Paraparesis (HAM/TSP) and Adult T cell leukemia/lymphoma (ATLL), in around 2–5% of the infected individuals. Host genetic background might play a role in disease progression. Several previous studies across many countries report HLA haplotype to be one such factor. Here, we sequenced HLA-A, -B and -C of 66 individuals by Sequence-Based Typing (SBT), and compared the frequency of different alleles among ATLL patients, HAM/TSP patients, asymptomatic carriers and non-infected individuals living in Argentina.ResultsThe frequency of HLA-A, -B and -C alleles largely matched that of the general population in Argentina. We identified HLA-A*02, HLA-B*35 and HLA-C*07 as associated to protection from ATLL (p = 0.031), susceptibility to HAM/TSP (p < 0.001) and susceptibility to ATLL (p = 0.017), respectively. We also found a strong correlation between high proviral load (PVL) and disease (p = 0.008), but were unable to identify any particular allele associated with high or low PVL.ConclusionsWe have found HLA-A*02, HLA-B*35 and HLA-C*07 to be associated to protection from ATLL (HLA-A*02) and susceptibility to HAM/TSP (HLA-B*35) or to ATLL (HLA-C*07), respectively. Whereas HLA-A*02 protection from ATLL has already been extensively described in other regions of the world, this is the first report that links HLA-B*35 and an increased susceptibility to HAM/TSP. As for HLA-C*07 it has previously been associated to susceptibility to HAM/TSP in other countries but in our population it has been linked to ATLL.

CD49d Is Upregulated in Circulating T Lymphocytes from HTLV-1-Infected Patients

Introduction: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive myelopathy associated with an inflammation of the central nervous system (CNS), being characterized by perivascular infiltration of inflammatory cells. HTLV-1-infected cells have the capacity to migrate through endothelial layers by enhancing adhesion receptor expression and corresponding ligands. T cells interact with the extracellular matrix via integrin receptors and these interactions affect both cell migration and proliferation. The importance of these interactions in retrovirus-induced diseases, however, remains less clear. Methods: Herein we studied the expression of 3 integrin alpha chains (CD49d, CD49e, and CD49f) on the membrane of T-cell subsets in patients infected by HTLV-1, both HAM/TSP patients and oligo/asymptomatic subjects who were asymptomatic or presented slight manifestations related to the virus infection. Results: We observed higher peripheral blood frequency of CD49d^hiCD4⁺ and CD49d^hiCD8⁺ T cells in HTLV-1-infected patients. Conclusion: Our findings suggest that the increased expression of adhesion molecules, such as CD49d on T lymphocytes from HTLV-1-infected patients may contribute to the pathogenesis of the disease, in both oligo/asymptomatic and HAM/TSP-infected subjects. Accordingly, it is conceivable that there is a potential use of CD49d as target for a therapeutic approach aiming at blocking migration of activated T cells from HTLV-1-infected patients into the CNS, thus avoiding the progression to HAM/TSP.

Comparision of the Frequency of Psychiatric Disorders in Patients with HTLV-1 Associated Myelopathy, Asymptomatic Carriers of Virus, and Healthy Control Group

Background: Sexual transmission of human T-lymphotropic virus 1 (HTLV-1) has been widely reported in different populations, including Khurasan in the northeast of Iran. Objectives: The present study compared the frequency of psychiatric symptoms and disorders in patients with HTLV-1 associated myelopathy, asymptomatic carriers of the virus, and healthy control group. Patients and Methods: This cross-sectional study had three groups, including HTLV-1 infected patients who visited HTLV-1 Clinic of Qhaem Hospital of Mashhad, Iran (30 individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis [HAM/TSP] and 45 in the asymptomatic group) and 41 HTLV-1 seronegative individuals in the control group. All subjects were screened by SCL90 for psychiatric symptoms, as well as motor disability levels according to Osame’s motor disability score (OMDS). Subjects who scored higher than the cut-off point in each screening evaluation attended structured clinical interviews (SCID) based on the fourth edition of the diagnostic and statistical manual of mental disorders (DSM-IV-TR). The data were analyzed by using one-way analysis of variance (ANOVA), the spearman correlation test and chi-square test, and SPSS19 was used for statistical analysis (P &lt; 0.05). Results: In general, 116 subjects were studied. The carrier and healthy groups were not significantly different in terms of psychiatric disorders. However, the frequencies of major depression (P = 0.011) and dysthymic disorders (P = 0.028) were higher in patients with myelopathy than healthy individuals. In addition, the frequency of the major depressive disorder was higher among patients with HAM/TSP than the HTLV-1 seronegative group (P = 0.002). The frequency distribution of major depression (P &lt; 0.001) and generalized anxiety (P = 0.018) was observed with an increase in OMDS. Conclusions: Regarding the high frequency of psychiatric symptoms, especially in patients with myelopathy, designing suitable psychiatric interventions seems essential in such patients.

Phylogenetic and phylodynamic study of Human T-cell lymphotropic virus Type 1 (HTLV-1) in Iran

Human T-lymphotropic virus type-1 (HTLV-1) is a retrovirus that causes the neurological disorder HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP) and/or adult T-cell leukemia/lymphoma (ATLL). Iran is one of the endemic regions of the HTLV-1 in the Middle East. To infer the origin of the virus in Iran and to follow the movements of human population and routes of virus spread to this country, phylogenetic and phylodynamic analyses were performed. To this purpose, the long terminal repeat (LTR) region of HTLV-1 was used. New LTR sequences were obtained from 100 blood samples which infected with HTLV-1. Moreover, all Iranian LTR sequences which have been reported so far, were obtained from GenBank database. Sequences were aligned and maximum-likelihood and Bayesian tree topologies were explored. After identification of Iranian specific cluster, molecular-clock and coalescent models were used to estimate time to the most recent common ancestor (tMRCA). Bayesian Skyline Plots (BSP), representing population dynamics HTLV-1 strains back to the MRCA, were estimated using BEAST software. Phylogenetic analysis demonstrated that the Iranian, Kuwaiti, German, Israelite and southern Indian isolates are located within the widespread “transcontinental” subgroup A clade of HTLV-1 Cosmopolitan subtype a. Molecular clock analysis of the Iranian cluster dated back their respective tMRCA to be 1290 AC with a 95% HPD confidence intervals (918, 1517). BSPs indicated a rapid exponential growth rate in the effective number of infections prior the 15th century. Our results support the hypothesis of a multiple introductions of HTLV-1 into Iran with the majority of introductions occurring in prior the 15th century, at the same time the Mongol invasion of Iran. Our results further suggest that HTLV-1 introduction into Iran was facilitated by the commercial/migratory linkage as known as the ancient Silk Road which linked China to Antioch (now in Turkey).

Prognosis Markers for Monitoring HTLV-1 Neurologic Disease.

Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated not only with some severe manifestations, such as HTLV-1-associated myelopathy (HAM) and ATLL, but also with other, less severe conditions. Some studies have reported neurologic manifestations that did not meet all the criteria for the diagnosis of HAM in individuals infected with HTLV-1; these conditions may later progress to HAM or constitute an intermediate clinical form, between asymptomatic HTLV-1 carriers and those with full myelopathy. This study evaluated the prognostic value and looked for a possible association of those parameters with the intermediate syndrome (IS) status and HAM status. Proviral load (PVL), spontaneous lymphoproliferation, interferon (IFN)-γ spontaneous production was quantified in samples of asymptomatic and HAM patients, as well as patients with IS. The critical age range was 50-60 years for IS outcome and more of 60 years for HAM outcome, with an increased risk of 2.5-fold for IS and 6.8-fold for HAM. IFN-γ was increased in patients with IS compared with asymptomatic carriers (ACs) (p = 0.007) and in patients with HAM compared with ACs (p = 0.03). Lymphoproliferation was increased in patients with HAM vs ACs (p = 0.0001) and patients with IS (p = 0.0001). PVL was similar between groups. IFN-γ has high specificity of prediction of subject remain asymptomatic compared with PVL and lymphoproliferation assay tests. IFN-γ has been shown to be a biomarker of progression to intermediate stage and to HAM. The association of other markers with manifestations associated with HTLV-1 infection that does not meet the HAM criteria should be verified.

Vestibular Evoked Myogenic Potential on Ocular, Cervical, and Soleus Muscles to Assess the Extent of Neurological Impairment in HTLV-1 Infection.

Introduction: Vestibular Evoked Myogenic Potential (VEMP) can be used to test central vestibular pathways from the midbrain to the lumbar spine, according to the muscle tested.Purpose: to compare the spinal cord alteration in individuals with HTLV-1-associated myelopathy (HAM) and with HTLV-1-asymptomatic infection using the VEMP recorded from different muscles.Methods: VEMP was recorded in 90 individuals of whom 30 had HAM, 30 were HTLV-1 asymptomatic carriers, and 30 negative controls. VEMP was recorded in the oculomotor muscle (oVEMP), testing the vestibulo-ocular reflex, and in the cervical muscle (cVEMP) and soleus muscle (sVEMP), testing the vestibulospinal reflex, respectively, in the cervical and in the lumbar spinal level. The type of stimulation was auditory for oVEMP and cVEMP, and galvanic for sVEMP. The compared variables were the latencies of the electrophysiological waves.Results: HTLV-1-asymptomatic group was similar to the controls regarding oVEMP (p = 0.461), but different regarding cVEMP (p < 0.001) and sVEMP (p < 0.001). HAM group has presented the worst latencies and was different from the HTLV-1-asymptomatic group in the VEMP of all the tested muscles (p < 0.001). The concomitant occurrence of VEMP alterations in the three recorded muscles of the same individual was found in 2 (6.7%) asymptomatic carriers and in 20 (66.7%) patients with HAM (p = 0.001). The analysis of VEMP alteration per group and per muscle has showed that, in HTLV-1-asymptomatic group, oVEMP was altered in 3 (10.0%) individuals, cVEMP in 10 (33.3%) and sVEMP in 13 (43.3%). In HAM group, oVEMP was altered in 23 (76.6%) individuals, cVEMP in 27 (90%), and sVEMP in 30 (100%).Conclusion: HTLV-1-neurological damage has followed an ascendant progression beginning at the lumbar spine in the stage of a clinically asymptomatic infection, whereas HAM has affected not only the spine, but also the midbrain.

Signs, meanings and practices of people living with human t-cell lymphotropic virus type 1 or tropical spastic myelopathy

BackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1) spreads silently in the world’s population and causes several syndromes. Among these, HTLV-1 associated myelopathy, also called tropical spastic paraparesis (HAM/TSP), affects the nervous system. It causes sensorimotor losses, spasticity, muscle weakness, voiding and sexual dysfunction, pain, and balance disorders. There is limited knowledge of the feelings, experiences, and coping mechanisms associated with this neglected disease. The objective of the present qualitative study was to investigate the signs, meanings, and practices of people with HAM/TSP, through narratives obtained from focus groups and individual semi-structured face-to-face interviews.ResultsThirty-eight individuals diagnosed with HAM/TSP participated in the study. The following categories and subcategories emerged from the participants: Signs—physical signs, symptoms, and discovery of the disease; Meanings—reaction to diagnosis and knowledge of disease, fears, and expectations; Practices—daily life, leisure, religious, and treatment activities.ConclusionsPeople with HAM/TSP suffer from symptoms that limit their social participation, and they are affected by complex and multidimensional feelings. This awareness can contribute to the implementation of public policies—focused on the real perspective of these patients—that provide more directed, empathic, and harmonious care for these individuals.

First Description of Seronegative HTLV-1 Carriers in Argentina.

In some areas of Argentina endemic for human T-lymphotropic virus type 1 (HTLV-1), tropical spastic paraparesis is frequent in subjects who lack antibodies against the virus; however, the relevance of this seronegative status in the country has not been investigated. In neighboring countries, HTLV-1 seronegative status has been described in patients with different diseases; however, data regarding features of seronegative HTLV-1 carriers are scarce. We investigated the seronegative status in 124 relatives of 28 HTLV-1 infected subjects from an endemic area in Northwest Argentina. Blood samples and clinical/epidemiological data were collected. Human T-lymphotropic virus type 1 infection was diagnosed by serology and long terminal repeat (LTR) sequence, env and tax gene detection. IgG anti-Tax HTLV-1 antibody, tax gene sequence, and DNA proviral load were also evaluated. Seventy-five percent of the 124 relatives were negative for HTLV-1/2 antibodies; 35.5% were also negative by molecular assays and 64.5% were negative for HTLV-1 LTR and env sequences, but positive for two sequences of HTLV-1 tax gene. Also, 35.7% of these subjects had IgG anti-Tax antibodies. The seronegative HTLV-1 status was significantly associated with male gender, youth, and sensory symptoms/autonomic nervous system dysfunction. High rates of seronegative symptomatic and asymptomatic HTLV-1 carriers in Argentina are described. The evidence highlights that HTLV-1 prevalence may be underestimated worldwide. Larger cohort studies are required to assess disease outcome in these seronegative subjects. Also, the findings emphasize the limitations of ongoing screening assays for diagnosis and blood safety. Therefore, algorithms for HTLV-1 diagnosis should include not only serological but also molecular assays.

The effect of home exercise on the posture and mobility of people with HAM/TSP: a randomized clinical trial.

Physical therapy has positive results in people with tropical spastic paraparesis (TSP). However, mobility and distance from rehabilitation centers limit the participation in outpatient programs. To evaluate the impact of a home exercise program on the posture and functional mobility of people with TSP. A randomized controlled trial comparing three groups of people who performed guided exercises from a guidebook for six months: supervised (SG), unsupervised (WG), and control (CG). Primary outcomes: postural angles (SAPO®) and functional mobility (TUG). gait parameters (CVMob®). The protocol described in the guidebook improved postural angles and functional mobility. There were also positive gait parameter effects (p<0.05). SG presented better responses than WG did, but both were preferable to CG. Home exercises oriented by a guidebook may benefit posture, functional mobility and gait parameters in people with TSP, and physiotherapist supervision can ensure better results.

Balance assessment in HTLV-1 associated myelopathy or tropical spastic paraparesis.

INTRODUCTION: A good rating of the device in people with HTLV-1 in this population is essential for accuracy in prescribing data (walking). Thus, this study aimed to analyze the counterpart assessment methods that are best suited to patients with human T-cell lymphotropic virus (HTLV)-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). METHODS: This cross-sectional study related stabilometric and kinematic variables of postural oscillations with Berg’s balance scale (BBS) and Timed Up and Go (TUG) in subjects with HAM/TSP compared to asymptomatic subjects. To assess the posterior and lateral postural projection, baropodometry and the Footwork® system was used, and the CVMob system was applied to kinematic parameters. The means comparison tests and correlations were applied with an alpha of 5%. RESULTS: Thirty-nine subjects (predominantly female) made up the sample. There was an increase in barodopometric oscillations, in the total oscillation area (p = 0.004), in the anteroposterior oscillation in the left (p = 0.015) and right views (p = 0.036), and in the lateral oscillation (p = 0.039) in the HAM/TSP group. Moderate correlations were found between oscillation baropodometry and the angular variation of the ankle, as well as with the BBS in the three angles and the TUG for lateral oscillation (p = 0.406). CONCLUSIONS: Each method has advantages and disadvantages, including cost accuracy. The best resources available at no additional cost for outpatient to use are the kinematic evaluation using a simple smartphone camera and free analysis software, and the TUG.

Center of gravity oscillations in HTLV-1-associated myelopathy/tropical spastic paraparesis

Abstract Introduction: Postural control in individuals with HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP) is usually compromised, which increases the risk of falls, makes it difficult to perform activities of daily living, and impairs the quality of life. The profile of the center of gravity oscillations in this population is unknown and may aid in clinical follow-up and research. Objective: To compare the stabilometric values between HAM/TSP and uninfected individuals and verify the existence of correlations between stabilometric variables and the Berg Balance Scale (BBS). Method: A cross-sectional observational study was performed with infected individuals, classified as defined and likely (WHO criteria), compared to accompanying persons and seronegative relatives. A baropodometry platform (Footwork®) was used to obtain the oscillation values of the body’s center of gravity in total oscillation area (TOA), anterior-posterior oscillation (APO) and lateral oscillation (LO). Mean values were correlated with BBS by Spearman’s Correlation (5% alpha). Approved by the ethical committee of Escola Bahiana de Medicina e Saúde Pública under Opinion 49634815.2.0000.5628. Results: An asymmetric distribution of all the stabilometric variables analyzed in the HAM/TSP population was found, different from the uninfected group (p &lt; 0.05). It was also possible to verify strong to moderate and inverse correlations between the variables of center of gravity oscillation with the scores obtained in BBS, especially for TOA and LO. Conclusion: People with HAM/TSP presented higher values for the center of gravity oscillations and these were correlated with the BBS in the balance evaluation.

Disabling neuropathic pain in tropical spastic paraparesis associated to the human T cells lymphotropic virus (HTLV-1). Case report

Disabling neuropathic pain in tropical spastic paraparesis associated to the human T cells lymphotropic virus (HTLV-1). Case report

Enigma of tropical spastic paraplegia.

Enigma of tropical spastic paraplegia.

Ocular vestibular evoked myogenic potential (VEMP) reveals mesencephalic HTLV-1-associated neurological disease.

PurposeVestibular Myogenic Evoked Potential (VEMP) evaluates vestibulo-ocular and vestibulo-collic reflexes involved in the function of the otolithic organs and their afferent pathways. We compared the results of cervical and ocular VEMP in HTLV-1 associated myelopathy (HAM) and HTLV-1-asymptomatic infection.Participants and methodsThis cross-sectional study included 52 HTLV-1-infected individuals (26 HAM and 26 asymptomatic carriers) and 26 seronegative controls. The groups were similar regarding age and gender. Participants underwent simultaneous ocular and cervical VEMP. The stimulus to generate VEMP was a low-frequency tone burst sound tone burst, with an intensity of 120 decibels normalized hearing level, bandpass filter from 10 to 1,500 Hertz (Hz), with 100 stimuli at 500 Hz and 50 milliseconds recording time. The latencies of the electrophysiological waves P13 and N23 for cervical VEMP and N10 and P15 waves for ocular VEMP were compared among the groups. The absence or delay of the electrophysiological waves were considered abnormal results.ResultsOcular VEMP was similar among the groups for N10 (p = 0.375) and different for P15 (p≤0.001). Cervical VEMP was different for P13 (p = 0.001) and N23 (p = 0.003). About ocular VEMP, in the HTLV-1-asymptomatic group, normal waves were found in 23(88.5%) individuals; in HAM group, normal waves were found in 7(26.9%). About cervical VEMP, 18(69.2%) asymptomatic carriers presented normal waves and only 3(11.5%) patients with HAM presented normal waves. Abnormalities in both VEMPs were found in 1(3.8%) asymptomatic carrier and in 16(61.5%) patients with HAM.ConclusionNeurological impairment in HAM was not restricted to the spinal cord. The mesencephalic connections, tested by ocular VEMP, have been also altered. Damage of the oculomotor system, responsible for eye stabilization during head and body movements, may explain why dizziness is such a frequent complaint in HAM.

Preclinical and clinical research on the toxic and neurological effects of cassava (Manihot esculenta Crantz) consumption.

Cassava (Manihot esculenta Crantz) is a tropical plant that is used as fresh food, processed food, or raw material for the preparation of flours with high nutritional value. However, cassava contains cyanogenic glycosides, such as linamarin and lotaustralin, that can trigger severe toxic effects and some neurological disorders, including motor impairment, cognitive deterioration, and symptoms that characterize tropical ataxic neuropathy and spastic epidemic paraparesis (Konzo). These alterations that are associated with the consumption of cassava or its derivatives have been reported in both humans and experimental animals. The present review discusses and integrates preclinical and clinical evidence that indicates the toxic and neurological effects of cassava and its derivatives by affecting metabolic processes and the central nervous system. An exhaustive review of the literature was performed using specialized databases that focused on the toxic and neurological effects of the consumption of cassava and its derivatives. We sought to provide structured information that will contribute to understanding the undesirable effects of some foods and preventing health problems in vulnerable populations who consume these vegetables. Cassava contains cyanogenic glycosides that contribute to the development of neurological disorders when they are ingested inappropriately or for prolonged periods of time. Such high consumption can affect neurochemical and neurophysiological processes in particular brain structures and affect peripheral metabolic processes that impact wellness. Although some vegetables have high nutritional value and ameliorate food deficits in vulnerable populations, they can also predispose individuals to the development of neurological diseases.

Home-based exercise programs for disabilities of walking activity caused by neurological disorders: Systematic Review with Meta-Analysis

INTRODUCTION: As increase life expectancy, the searches for conducts to improve functional independence in chronically altered conditions as is common in the neurological dysfunction. OBJECTIVES: To evaluate the effect of therapeutic home based exercise programs (HBE) on impairment of walking activity due to stroke, Parkinson's disease (PD), multiple sclerosis and HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). METHODS: data sources PubMed, Scielo, Pedro, Cochrane Library; available in English, Portuguese, Spanish, German or French languages; no time restrictions; selection made by two independent researchers, in three stages; included Clinical Trials with interventions of HBE Programs for adults with gait or balance disabilities arising from the above neurological conditions; gait speed or distance, strength, balance, mobility, functionality and functional independence were the variables; methodological quality with PEDro scale; PICOS strategy guided the extraction date. Weighted mean differences (WMD), 95% confidence intervals (CI), and the heterogeneity assessed by the I2 test with RevMan 5.3 program. Results in balance (WMD 2.8; CI 1.5; 4.1) and in cardiorespiratory capacity (WMD 29.3m; IC 8.3; 50.2) for people with stroke are effectiveness. For people with Multiple Scleroses there is improvement in physiological profile (WMD -1.3; CI -0.5; 2.0) and mobility (WMD -3.3; CI -5.1; -1,4). CONCLUSIONS: The HBE is effective on walking activity, improve performance and functional mobility in neurological impairments. Is suggested HBE on public health to includ elements for management of disabilities on the programs and the use of functional scales such as WHODAS to compare the same disability in different neurological disorders.

HTLV-1 Dysregulates IL-6 and IL-10-JAK/STAT Signaling and Induces Leukemia/Lymphoma of Mature CD4+ T Cells with Regulatory T-Cell-like Signatures

Human T-cell leukemia virus, type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and chronic inflammatory diseases (e.g., HTLV-1 associated myelopathy, uveitis). Among viral genes encoded in the HTLV-1 provirus, HTLV-1 bZIP factor (HBZ) is the most important gene for its pathogenesis, since HBZ is constantly expressed in all ATL cases, and has a potential to enhance T-cell proliferation. We generated HBZ transgenic (Tg) mice and found that almost all mice developed systemic inflammation, such as dermatitis, and about 40% of mice suffered from T-cell lymphoma. In addition, this mouse demonstrates the similar immunophenotypes to HTLV-1-infected subjects, such as increase of effector/memory and Foxp3-expressing regulatory T cells (Tregs), indicating that it is a good animal model to analyze the molecular mechanisms of pathogenesis by HTLV-1. There is a clear correlation between the severity of inflammation and the incidence of T-cell lymphoma, suggesting that some immune factors are closely involved in oncogenesis by HBZ. Recent studies showed that several pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-6 (IL-6), participate in not only inflammation but also tumor development. Especially, IL-6 has been reported to play important roles in oncogenesis, tumor progression, angiogenesis and migration. To clarify the roles of IL-6 in HBZ-mediated lymphomagenesis, we crossed HBZ-Tg mice with IL-6 knockout (KO) mice. Contrary to our hypothesis, inflammation was exacerbated, and incidence of T-cell lymphomas was markedly increased in HBZ-Tg/IL-6KO mice. In the pathological analysis of the lymphoma tissues, the percentage of Foxp3+ cells were much higher in HBZ-Tg/IL-6KO mice than in HBZ-Tg mice. Moreover, flow cytometric analysis also showed that CD4+Foxp3+ T cells were increased in spleens from HBZ-Tg/IL-6KO mice compared with HBZ-Tg mice or WT mice. Since IL-6 inhibits TGF-beta-induced Foxp3 expression and subsequently suppresses differentiation to Tregs, our results suggest that depletion of IL-6 induces aberrant differentiation of CD4+ T cells toward Treg-like cells in HBZ-Tg mice and accelerates lymphomagenesis of this subset. RNA-seq and flow cytometric analyses revealed that expression of IL-10 was significantly higher in CD4+ T cells of HBZ-Tg/IL-6KO than HBZ-Tg. Importantly, IL-10 accelerated the proliferation of CD4+ T cells of HBZ-Tg whereas it did not influence control T cells. We also found that HBZ interacted with both STAT1 and STAT3, which are critical transcription factors in IL-10-JAK/STAT signaling pathways, and enhanced their transcriptional activities. Foxp3-expressing T cells and IL-10 are known to be immune-suppressive, but these results indicate that increased Foxp3-expressing T cells and activation of IL-10-JAK/STAT signaling are associated with inflammation and lymphomagenesis by HBZ in vivo. Our results suggest that IL-6 and IL-10 have suppressive and promoting effects on HBZ-induced pathogenesis, respectively. It has been reported that progression of HTLV-1-associated diseases was observed in several HTLV-1 carriers after administration of anti-IL-6R antibody, Tocilizumab. Inhibition of IL-6/IL-6R signaling and consequent activation of Foxp3/IL-10/JAK/STAT axis seem to be important for HTLV-1 pathogenesis. Disclosures Ohshima: Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene Corp.: Honoraria, Research Funding; NEC Corp.: Research Funding; SRL, Inc.: Consultancy. Matsuoka:Kyowa Kirin Co., Ltd.: Research Funding; Bristol-Myers Squibb Corp.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria.

Tropical spastic paraparesis threat of human Type 1 T-cell lymphotropic virus: Case report of one patient from San José Hospital, Bogotá, Colombia 2019

Tropical Spastic Paraparesis is a disease caused by the human lymphotropic virus of type 1 cells (HTLV-1). It is characterized by low back pain, progressive weakness of lower limbs, and bladder dysfunction of early appearance which can carry out a permanent physical limitation. However, only 2-3% cases patients with the human lymphotropic virus of type 1 cells, show these set of symptoms. We present a case of a 42 year-old female patient, originally from the Cachipay, Cundinamarca, Colombia with a clinical course that started when she was 18 years old. Other possible diagnoses were ruled out (table 1), and the disease was confirmed with a serum test and cerebrospinal fluid of the virus. The thoracic and lumbar simple resonance sequence T2 sagittal section had discrete diffuse hyperintensity of the lateral cords and atrophy from the upper thoracic segment T1 to T12 (figure 1). Tropical Spastic Paraparesis is a disease challenging to diagnose due to multiple differential diagnoses. Initially in Colombia, this disease was only detected in Cauca, Pacific Coast, and Valle del Cauca. However, sporadic cases have been described in other regions such as Risaralda and Antioquia. Notably, there have been no previously described cases in the state of Cundinamarca. It may suggested that Tropical Spastic Paraparesis has continued to spread due to no preventive measures to contain the disease.

Hormonal and Psychogenic Risk Factors for Erectile Dysfunction in Men with HTLV-1

IntroductionErectile dysfunction (ED) is associated with neurological damage due to human T-lymphotropic virus 1 (HTLV-1) infection, but hormonal and psychogenic factors also cause ED. AimTo evaluate the association of psychogenic and hormonal factors with ED in men infected with HTLV-1. MethodsIn this cross-sectional study, we compared total testosterone, follicle stimulating hormone, luteinizing hormone, prolactin, anxiety symptoms, depressive symptoms, and neurologic manifestations in HTLV-1-infected men with or without ED. The International Index of Erectile Function was used to determine the degree of ED. Participants were grouped according to Osame’s Motor Disability Scale and the Expanded Disability Status Scale: HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP), probable HAM/TSP, or HTLV-1 carrier. Chi-square and Fisher’s exact tests were used to compare the groups, and regression analyses were used to show predictors of ED. Main Outcome MeasureSexual hormonal levels, psychogenic factors, and neurologic disabilities were found to be associated with ED. ResultsED was associated with age older than 60 years (P < .001), degree of neurologic involvement (P < .001), depression (P = .009), and anxiety (P = .008). In the multivariate analyses, only age and degree of neurological injury remained as risk factors for ED. Clinical ImplicationsNeurological manifestations are a stronger predictor of ED than hormonal and psychogenic factors in HTLV-1-infected men. Strengths & LimitationsThe statistical power of the study was limited due to the low number of participants, but neurologic manifestations were clearly associated with ED. There was no strong association between hormonal and psychogenic factors and ED. ConclusionHormonal and psychogenic factors did not show a strong association with ED in individuals with HTLV-1, but neurological manifestations were strongly associated with ED in these individuals.de Oliveira CJV, Neto, JAC, Andrade RCP, et al. Hormonal and Psychogenic Risk Factors for Erectile Dysfunction in Men with HTLV–1. J Sex Med 2019; 16:1763–1768.