A case of unilateral shoulder joint hydrarthrosis with wild-type amyloidogenic transthyretin amyloidosis.

Wild-type amyloidogenic transthyretin (ATTR) amyloidosis, known as systemic senile amyloidosis (SSA), is an age-related nonhereditary amyloidosis, which is known to cause cardiomyopathy and carpal tunnel syndrome (CTS). Herein, we report a case of unilateral hydrarthrosis with arthritis of the right shoulder joint in an 82-year-old Japanese housewife who has a seven year history of polyneuropathy due to an unknown aetiology. At first, her joint pain was thought to be caused by overuse of her right upper arm. Despite treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and repeated arthrocentesis, her symptoms did not improve. She then visited our hospital, where magnetic resonance imaging (MRI) of her right shoulder suggested synovitis and hydrarthrosis. She also had an arthroscopic synovectomy of the right shoulder joint. The pathological testing revealed a diagnosis of non-specific arthritis with amyloidosis. After further pathological examination, wild-type ATTR was identified and she was diagnosed with senile amyloidosis.

Role of Integrin Signaling Activation on the Development of Human T Cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis: Its Relationship to HTLV-1-Infected CD4+ T Cell Transmigrating Activity into the Tissues.

The main clinical feature of human T cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is slowly progressive spastic paraparesis with bladder dysfunction. HAM/TSP is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction of surrounding tissues by the interaction between infiltrated Th1-like, HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ cytotoxic T cells (CTL), is probably critical for the induction of chronic inflammation. Although the HTLV-1-infected CD4+ T cells in HAM/TSP appear to play a crucial role in the initial pathogenesis of HAM/TSP, the exact mechanisms of how these cells acquire their function as the first responders in the pathogenesis of HAM/TSP still remain unresolved. Herein, we propose the importance of the activation of both outside-in signals from integrin signaling and inside-out signals for integrin signaling in the HTLV-1-infected CD4+ T cells of HAM/TSP patients.

Pentosan polysulfate treatment ameliorates motor function with increased serum soluble vascular cell adhesion molecule-1 in HTLV-1-associated neurologic disease.

The main therapeutic strategy against human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) characterized by lower extremity motor dysfunction is immunomodulatory treatment, with drugs such as corticosteroid hormone and interferon-α, at present. However, there are many issues in long-term treatment with these drugs, such as insufficient effects and various side effects. We now urgently need to develop other therapeutic strategies. The heparinoid, pentosan polysulfate sodium (PPS), has been safely used in Europe for the past 50 years as a thrombosis prophylaxis and for the treatment of phlebitis. We conducted a clinical trial to test the effect of subcutaneous administration of PPS in 12 patients with HAM/TSP in an open-labeled design. There was a marked improvement in lower extremity motor function, based on reduced spasticity, such as a reduced time required for walking 10 m and descending a flight of stairs. There were no significant changes in HTLV-I proviral copy numbers in peripheral blood contrary to the inhibitory effect of PPS in vitro for intercellular spread of HTLV-I. However, serum soluble vascular cell adhesion molecule (sVCAM)-1 was significantly increased without significant changes of serum level of chemokines (CXCL10 and CCL2). There was a positive correlation between increased sVCAM-1and reduced time required for walking 10 m. PPS might induce neurological improvement by inhibition of chronic inflammation in the spinal cord, through blocking the adhesion cascade by increasing serum sVCAM-1, in addition to rheological improvement of the microcirculation. PPS has the potential to be a new therapeutic tool for HAM/TSP.

Efficacy of prosultiamine treatment in patients with human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: results from an open-label clinical trial.

BACKGROUND: Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy characterized by motor dysfunction of the lower extremities and urinary disturbance. Immunomodulatory treatments are the main strategy for HAM/TSP, but several issues are associated with long-term treatment. We conducted a clinical trial with prosultiamine (which has apoptotic activity against HTLV-I-infected cells) as a novel therapy in HAM/TSP patients. METHODS: We enrolled 24 HAM/TSP patients in this open-label clinical trial. Prosultiamine (300 mg, orally) was administered once daily for 12 weeks. We monitored changes in the motor function of the lower extremities and urinary function as well as copy numbers of the HTLV-I provirus in peripheral blood mononuclear cells (PBMCs). RESULTS: Improvement in the motor function of the lower extremities based on a reduction in spasticity (for example, decrease in time required for walking and descending a flight of stairs) was observed. In an urodynamic study (UDS), bladder capacity and detrusor pressure and then maximum flow rate increased significantly. Detrusor overactivity and detrusor-sphincter dyssynergia improved in 68.8% and 45.5% of patients observed at pretreatment, respectively. Improvement in UDS corresponded with improvements in the score of nocturia-quality of life questionnaire. HTLV-I proviral copy numbers in PBMCs decreased significantly (approximately 15.4%) compared with pretreatment levels. CONCLUSIONS: These data suggest that prosultiamine can safely improve motor dysfunction of the lower extremities and urinary disturbance as well as reduce HTLV-I provirus levels in peripheral blood. It therefore has potential as a new therapeutic tool for HAM/TSP patients. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number, UMIN000005969. Please see related commentary: http://www.biomedcentral.com/1741-7015/11/183.

Therapeutic strategies in HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic progressive myelopathy characterized by bilateral pyramidal tracts involvement with sphincteric disturbances. HTLV-I infects approximately 10-20 million people worldwide. There are large endemic areas in southern Japan, the Caribbean, Central and South America, the Middle East, Melanesia, and equatorial regions of Africa. Since the primary neuropathological feature of HAM/TSP is chronic inflammation caused by HTLV-I infection in the spinal cord, various treatments focusing on immunomodulatory or anti-viral effects were performed for HAM/TSP patients until now. However, there are still many of problems, such as insufficient effects, side effects and expensive costs in long-term treatments, etc., in these treatments. Therefore, an ideal therapeutic strategy against HAM/TSP is still not established yet. Although only a small proportion of HTLV-I-infected individuals develops HAM/TSP, neurological symptoms are certainly progressive once myelopathy develops, leading to deterioration of the quality of life. Therefore, we now need the therapeutic regimens to protect the development, or be able to commence the treatments as soon as possible after the development safely and inexpensively even in long-term course or lifelong course of treatment. As HTLV-I-infected CD4(+) T cells are the first responders in the immunopathogenesis of HAM/TSP, the ideal treatment is the elimination of HTLV-I-infected cells from the peripheral blood. In this article, we will review the therapeutic strategies against HAM/TSP up to now and will introduce our new therapeutic approach focusing on the targeting of HTLV-I-infected cells in HAM/TSP patients.

Disulfide-mediated apoptosis of human T-lymphotrophc virus type-I (HTLV-I)-infected cells in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.

BACKGROUND: This study was conducted to construct a basis for a therapeutic strategy against human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) using a compound that contained a disulfide moiety, prosultiamine, which is a homologue of allithiamine originally synthesized by allicin and thiamine-thiol, for the targeting of HTLV-I-infected cells. METHODS: First, we analysed the apoptotic pathway in allicin or prosultiamine treatment against an HTLV-I-infected T-cell line (HCT-1), derived from an HAM/TSP patient, by flow cytometry and western blot. Second, we evaluated the effect of targeting HTLV-I-infected cells in a prosultiamine in vitro treatment and in a clinical trial in HAM/TSP patients by quantitative PCR analysis of HTLV-I proviral load. RESULTS: Prosultiamine, like allicin, induced caspase-dependent apoptosis against HCT-1 cells. The fact that the loss of mitochondrial membrane potential was recovered in z-VAD-fmk-pretreated HCT-1 cells with prosultiamine treatment suggested that prosultiamine can induce caspase-dependent apoptosis through the mitochondrial pathway. On the basis of data showing that prosultiamine in vitro treatment against peripheral blood CD4(+) T-cells of HAM/TSP patients induced a significant decrease of HTLV-I proviral copy numbers by apoptosis of HTLV-I-infected cells, we treated six HAM/TSP patients with intravenous administration of prosultiamine for 14 days. As a result of this treatment, the copy numbers of HTLV-I provirus in peripheral blood decreased to approximately 30-50% of their pretreatment levels with some clinical benefits in all patients. CONCLUSIONS: Our results suggest that prosultiamine has the potential to be a new therapeutic tool that targets HTLV-I-infected cells in HAM/TSP.

HTLV-I production based on activation of integrin/ligand signaling in HTLV-I-infected T cell lines derived from HAM/TSP patients.

OBJECTIVE: Activity of integrin/ligand signaling leading to activation of small GTPases might regulate the efficiency of cell-to-cell spread of human T lymphotropic virus type I (HTLV-I) through the virological synapse. We compared both activity of small GTPases and involvement of integrin/ligand signaling in extracellular release of HTLV-I virions between each three HTLV-I-infected T cell lines derived from HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and from other origins as a control. METHODS: Activity of small GTPases (Rho, Rac and Cdc42) was analyzed by pull-down assay with suppressive effect of both HTLV-I production and HTLV-I tax mRNA expression by anti-integrin-blocking antibodies. RESULTS: All small GTPases were strongly activated in all cell lines derived from HAM/TSP patients, but not in control cell lines except one cell line. Treatment of all cell lines derived from HAM/TSP patients, but not all control cell lines, with anti-integrin-blocking antibodies significantly suppressed the level of HTLV-I p19 antigen in culture supernatants without downregulation of HTLV-I tax mRNA expression. CONCLUSION: Significant involvement with integrin/ligand signaling in extracellular release of HTLV-I virions in cell lines derived from HAM/TSP patients suggests that HTLV-I-infected cells in HAM/TSP patients have the potential for the efficient spread of HTLV-I to uninfected cells.

Blockade of IL-2 receptor suppresses HTLV-I and IFN-gamma expression in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.

OBJECTIVE: Th1 activation based on a high HTLV-I proviral load is one of the characteristic immunological abnormalities in the peripheral blood lymphocytes of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). To clarify the cause of this abnormality with the potential to be one of the therapeutic targets, we analyzed the involvement of interleukin-2 (IL-2)/IL-2 receptor (IL-2R) signaling in HTLV-I and interferon-gamma (IFN-gamma), which is a representative Th1 cytokine, expression in peripheral blood CD4(+) T cells from HAM/TSP patients. PATIENTS AND METHODS: Twelve patients with HAM/TSP were included in the study. After the peripheral blood CD4(+) T cells were treated in cultures under the presence of each anti-IL-2Ralpha, beta,and gamma blocking antiboby for 48 hours, both HTLV-I p19 antigen and IFN-gamma levels in the culture supernatants were measured using ELISA methods. To check the influence on cell proliferation under these culture conditions, the numbers of viable cells were simultaneously determined by MTS assay. RESULTS: Treatment with anti-IL-2Ralpha blocking antibody, but not anti-IL-2Rbeta or anti-IL-2Rgamma blocking antibody, suppressed HTLV-I p19 antigen expression levels. In addition, treatment with all types of anti-IL-2R blocking antibodies also suppressed IFN-gamma expression levels. All of the types of anti-IL-2R blocking antibodies did not inhibit the proliferation. CONCLUSION: These results indicate that IL-2/IL-2R signaling is involved in HTLV-I and IFN-gamma expression on peripheral blood CD4(+) T cells from HAM/TSP patients, suggesting that the interruption of this signaling has therapeutic potential against HAM/TSP in patients with the focus on the down-regulation of Th1 activation based on a high HTLV-I proviral load in the peripheral blood.

Involvement of p38 MAPK signaling pathway in IFN-gamma and HTLV-I expression in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.

We analyzed the relationship between the expression of interferon (IFN)-gamma and HTLV-I p19 antigen and activation of p38 mitogen-activated protein kinase (p38 MAPK) in two HTLV-I-infected T cell lines derived from two patients (HCT-1 and HCT-4) with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and three HTLV-I-infected T cell lines derived from three patients with adult T cell leukemia (ATL). Expression of phosphorylated (activated)-p38 MAPK was markedly increased concomitant with high levels of both IFN-gamma and HTLV-I p19 antigen expression in both HCT-1 and HCT-4 compared with cell lines derived from ATL patients. Treatment with SB203580, a specific inhibitor of p38 MAPK, suppressed IFN-gamma and HTLV-I p19 antigen expression levels in HCT-1, HCT-4 and peripheral blood CD4(+) T cells of HAM/TSP patients. These findings strongly suggest that activation of p38 MAPK signaling pathway is involved in the up-regulation of IFN-gamma expression with high HTLV-I proviral load in HAM/TSP patients.

Increased mRNA expression of Th1-cytokine signaling molecules in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.

Expression of inflammatory cytokines derived from Th1 cell population is increased in patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It has been shown that cytokine signaling molecules, including transcription factors T-bet and GATA-3, interleukin-12 receptor beta 2 (IL-12R beta 2) and suppressors of cytokine signaling (SOCS), such as SOCS1, are important in differentiation of naive T cells into Th1 helper T cells. To assess the immunological status from the stand-point of cytokine signaling in patients with HAM/TSP, we analyzed mRNA expression of these cytokine signaling molecules in peripheral blood mononuclear cells using quantitative RT-PCR. Twenty-eight HAM/TSP patients, nine HTLV-I-infected individuals without HAM/TSP and twenty-two HTLV-I-uninfected individuals were included in this study. Expression of T-bet, GATA-3, IL-12R beta 2 and SOCS1 was significantly increased in HAM/TSP patients in comparison with HTLV-I-uninfected individuals. In contrast, expression of SOCS3, a marker for Th2 cells, was significantly decreased in HTLV-I-infected individuals. These results indicate that HAM/TSP patients are associated with increased Th1 and decreased Th2 cytokine signaling activities.

[A case of Creutzfeldt-Jakob disease with a point mutation of prion protein at codon 180].

A 67-year-old woman was admitted to our hospital with progressive aphasia. There was no family history of similar diseases or any history of dura transplantation. Cranial magnetic resonance imaging (MRI) showed high signal areas in the temporal and parietal cortex predominantly on the left side on both T2-weighted images and on diffusion-weighted images. There were no periodic synchronous discharges observed on the electroencephalogram. As prion protein gene codon 180 point mutation (Val/Ile) was detected, we diagnosed her as having Creutzfeldt-Jakob disease (CJD). The characteristics of CJD of this type differ from those of sporadic CJD. To date, few papers on CJD with point mutation of codon 180 have been reported from Japan.

Increased sialyl Lewis(x) antigen-positive cells mediated by HTLV-1 infection in peripheral blood CD4(+) T lymphocytes in patients with HTLV-1-associated myelopathy.

Sialyl Lewis(x) antigen-positive (sLe(x+)) cells play an important role in the first step of transmigration of T lymphocytes through vascular endothelial cells into tissues. We compared the proportion of sLe(x+) cells in peripheral blood CD4(+) T lymphocytes between patients with HTLV-1-associated myelopathy (HAM) and control patients, by using flow cytometry. The percentage of sLe(x+) cells in peripheral blood CD4(+) T lymphocytes was significantly higher in HAM patients compared to control patients. Interferon-gamma (IFN-gamma), but not interleukin-4 (IL-4), production by the sLe(x+) cell population of peripheral blood CD4(+) T lymphocytes was significantly higher in HAM patients than in control patients. In addition, comparison of the HTLV-1 proviral load between sLe(x+) and sLe(x-) cells in peripheral blood CD4(+) T lymphocytes of HAM patients showed that the HTLV-1 proviral load was significantly higher (two- to eight-fold), concomitant with enhanced IFN-gamma production, in the sLe(x+) than in the sLe(x-) cell population. Our findings indicate that the sLe(x+) cell population, which has features of activated Th1 cells with up-regulated expression of E- and P-selectin ligands mediated by HTLV-1 infection, is increased in peripheral blood CD4(+) T lymphocytes in HAM patients, suggesting their involvement in transmigration of peripheral T lymphocytes from the peripheral blood into tissues.

Up-regulation of interleukin-12 receptor expression in peripheral blood mononuclear cells of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.

We previously reported elevated levels of serum interleukin-12 (IL-12) in association with increased interferon-gamma (IFN-gamma) levels in patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The interaction between IL-12 and IL-12 receptor (IL-12R) plays an important role in differentiation of the T helper type 1 (Th1) phenotype. In this study, we further examined the IL-12/IL-12R axis by investigating the expression of IL-12R and CD40 ligand (CD40L) in peripheral blood mononuclear cells (PBMC) of 18 HAM/TSP patients, and comparing the levels with those in 25 patients with other neurological disorders, including 4 anti-HTLV-I-seropositive carriers as controls. Two-color analysis by flow cytometry revealed a significantly high percentage of IL-12R beta1+ cells in CD4+ T lymphocytes in HAM/TSP patients compared to the control. Furthermore, IL-12R beta2 mRNA expression in PBMC was detected by reverse-transcriptase polymerase chain reaction in 6 of 18 HAM/TSP patients, but not in any control patients. In contrast, there was no significant difference between the percentage of CD40L+ cells in CD4+ T lymphocytes in HAM/TSP and control patients. Our results suggest Th1 immune activation in patients with HAM/TSP, which leads to chronic inflammation in the spinal cord, mediated by dysregulation of the IL-12/IL-12R axis rather than of the CD40/CD40L interaction.

[Successful treatment in a patient with a focal form of stiff-person syndrome using plasma exchange and intravenous immunoglobulin therapy].

We report a 42-year-old female with continuous muscle stiffness and painful muscle spasms of the right leg. The symptoms developed suddenly and worsened over the week after onset. At hospitalization, the right leg had a fixed posture of extension and the foot was plantar-flexed and internally rotated. Neurological examination revealed hyperreflexia of the right knee with positive Chaddock's sign, and stiffness and painful spasms located in the right leg, exaggerated by sudden auditory and tactile stimuli or by emotional stress. She could not walk due to her stiffness. There were no signs of rigidity in the left leg, upper extremities, or truncal muscles. Electrophysiological examinations revealed continuous muscle discharge. High titers of anti-glutamic decarboxylase (GAD) antibodies were detected in serum (140,000 U/ml) and cerebrospinal fluid (1,347 U/ml), confirming that the patient suffered from stiff-leg syndrome. Systemic evaluation revealed no malignant neoplasm, but revealed euthyroid Hashimoto's disease. Stiff-leg syndrome in this case was unresponsive to pharmacotherapy with diazepam and was unchanged for the first month of hospitalization. Plasma exchange therapy alleviated the clinical symptoms and decreased the anti-GAD antibody titer. After IVIg therapy, the symptoms and signs have dramatically disappeared to date but the titer of anti-GAD antibodies in serum recurred after an initial fall. To our knowledge, this is the first case of stiff-leg syndrome in Japan.