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Annals of Indian Academy of Neurology 2022
PubMed: 36911454
DOI: 10.4103/aian.aian_658_22 -
Journal of Virology Nov 2022Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis...
Establishment of a Cynomolgus Macaque Model of Human T-Cell Leukemia Virus Type 1 (HTLV-1) Infection by Direct Inoculation of Adult T-Cell Leukemia Patient-Derived Cell Lines for HTLV-1 Infection.
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the precise mechanisms leading to HTLV-1 chronic infection and the onset of the diseases have remained unclear, and effective vaccines for inhibiting the infection and the progression of pathogenesis have therefore not been developed. The use of a nonhuman primate (NHP) model is thought to be important for revealing the mechanisms of the progressive status and for the development of prevention procedures. In this study, we developed a cynomolgus macaque (CM) model of HTLV-1 infection by direct intravenous inoculation of HTLV-1-producing cells derived from ATL patients. The cell line used for infection, ATL-040, was selected as the most infectious one in our cell line library. CMs inoculated intravenously with 1 × 10 ATL-040 cells per animal became persistently infected with HTLV-1, as shown by the HTLV-1 provirus load (PVL) in peripheral blood mononuclear cells and HTLV-1-specific antibodies (2/2 animals). One CM inoculated intravenously with 1 × 10 ATL-040 cells did not have detectable PVLs despite the fact that anti-HTLV-1 antibodies were maintained for more than 2 years. Furthermore, immunological approaches, including CD8 T cell depletion prior to infection (3/3 animals) and intrathecal inoculation (3/3 animals), led to increased proviral loads in the cynomolgus monkeys. The present method and the cynomolgus monkey model of HTLV-1 infection will be beneficial for immunological and virological studies on HTLV-1 aiming at the development of anti-HTLV-1 prophylactic vaccines and therapy drugs. HTLV-1 was discovered in the 1980s as the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. However, the precise mechanisms leading to HTLV-1 chronic infection and the onset of the diseases still remain unidentified. Thus, no effective vaccines to inhibit the infection and the progressive of pathogenesis have been developed. The use of appropriate animal models is essential for understanding HTLV-1 infection and pathogenesis. In order to establish a new nonhuman primate model for studies on HTLV-1 infection, cynomolgus monkeys were infected with HTLV-1 under a variety of experimental conditions. Our method, using a cell line generated from an ATL patient as a source of HTLV-1, was able to establish HTLV-1 infection in monkeys with a 100% success rate. This cynomolgus macaque model of HTLV-1 infection will contribute to the elucidation of HTLV-1 infection and its associated disease development.
Topics: Animals; Humans; Cell Line; Human T-lymphotropic virus 1; Leukemia-Lymphoma, Adult T-Cell; Leukocytes, Mononuclear; Macaca fascicularis; Paraparesis, Tropical Spastic; Proviruses; Disease Models, Animal
PubMed: 36314828
DOI: 10.1128/jvi.01339-22 -
Medicina (Kaunas, Lithuania) Oct 2022ATL is a rare but a highly aggressive T-cell neoplasm associated with human T-cell leukemia virus-1 (HTLV-1) infection. Human T-cell lymphotropic virus type-1 (HTLV-1)... (Review)
Review
ATL is a rare but a highly aggressive T-cell neoplasm associated with human T-cell leukemia virus-1 (HTLV-1) infection. Human T-cell lymphotropic virus type-1 (HTLV-1) is a oncogenic retrovirus responsible for the development of adult T-cell leukemia (ATL), but also for other non-malignant diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 has a higher prevalence in Japan, the Caribbean, South America, intertropical Africa, Romania, and northern Iran. ATL patients can have an extensive spectrum of neurological manifestations. Numerous factors can be implicated, such as central nervous system infiltrates, neurolymphomatosis, complications to medication or allogeneic stem cell transplantation, HAM/TSP, infections, metabolic disturbances. The neurological complications are not always easy to recognize and treat. Thus, this review underlines the necessity of a multidisciplinary approach in ATL patients with neurological symptomatology.
Topics: Adult; Humans; Leukemia-Lymphoma, Adult T-Cell; Paraparesis, Tropical Spastic; Human T-lymphotropic virus 1; Central Nervous System; Africa
PubMed: 36363509
DOI: 10.3390/medicina58111553 -
Neurological Sciences : Official... Feb 2022Mutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes...
Mutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation in POLR3A. Here, we present 10 patients from 8 unrelated families with POLR3A-related late-onset spastic ataxia, all harboring the c.1909 + 22G > A variant. Most of them showed an ataxic-spastic picture, two a "pure" cerebellar phenotype, and one a "pure" spastic presentation. The non-neurological findings typically associated with POLR3A mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The POLR3A mutations present in this cohort were the c.1909 + 22G > A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14-18. Interestingly, this patient had the most "complex" presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset POLR3A-related disorders, and therefore further expand the phenotype.
Topics: Ataxia; Child; Humans; Mutation; Optic Atrophy; Paraparesis, Spastic; Phenotype; RNA Polymerase III; Spastic Paraplegia, Hereditary; Spinocerebellar Ataxias
PubMed: 34296356
DOI: 10.1007/s10072-021-05462-1 -
Journal of the American Veterinary... Oct 2017
Topics: Animals; Diagnosis, Differential; Dog Diseases; Dogs; Histiocytic Sarcoma; Lumbar Vertebrae; Magnetic Resonance Imaging; Male; Neurologic Examination; Paraparesis; Spinal Cord Neoplasms
PubMed: 28959925
DOI: 10.2460/javma.251.8.897 -
Scientific Reports Aug 2019The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus from the Retroviridae family that infects cluster of differentiation 4 (CD4) T-lymphocytes and...
The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus from the Retroviridae family that infects cluster of differentiation 4 (CD4) T-lymphocytes and stimulates their proliferation. A severe consequence of this infection can be the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is associated with a progressive demyelinating disease of the upper motor neurons. The HAM/TSP conditions frequently present with neurological complaints such as gait impairment, sphincter disturbances, and several sensory losses. We compared findings from the posturographic evaluation from the asymptomatic HTLV-1 infected subjects, HTLV-1 infected subjects having HAM/TSP, and control group database. A force plate was used to record the postural oscillations. Analysis of variance and multivariate linear discriminant analysis were used to compare the data obtained from the three groups of participants. In general, HAM/TSP patients had worse postural balance control than did the HTLV-1 patients and the controls (p < 0.05). We found that in six out of ten parameters of the postural balance control, there was a gradual increase in impairment from control to HTLV-1 to HAM/TSP groups. All parameters had higher values with the subject's eyes closed. The multivariate linear discriminant analysis showed there was a reasonable difference in results between the control and HAM/TSP groups, and the HTLV-1 group was at the intersecting area between them. We found that HAM/TSP patients had worse balance control than did HTLV-1 infected patients and the control group, but asymptomatic HTLV-1 infected patients represent an intermediate balance control status between controls and HAM/TSP patients. Posturographic parameters can be relied on to identify subtle changes in the balance of HTLV-1 patients and to monitor their functional loss. HTLV-1 is a tropical disease that can be transmitted by sexual intercourse, blood transfusion, and breast-feeding. Some infected subjects develop an HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a condition characterized by spasticity, weakness in lower limbs, and difficulty in walking long distances and going up and down the stairs, besides the history of falls. We compared the body oscillations using a force plate to investigate the postural balance control. HTLV-1 infected patients had imbalance that could be identified by posturographic parameters. Patients with HAM/TSP clearly had balance impairments, while HTLV-1 without HAM/TSP had a subtle impairment that was not seen on clinical scales, suggesting that these patients were in the middle between healthy and HAM/TSP patients, and carried a risk of developing severe imbalance postural control. We suggest that more research should be done with the aim to identify the subtle signs in asymptomatic HTLV-1 patients to investigate if this group of patients need attention similar to the HAM/TSP patients.
Topics: Adult; Asymptomatic Infections; Case-Control Studies; Female; HTLV-I Infections; Healthy Volunteers; Human T-lymphotropic virus 1; Humans; Male; Middle Aged; Paraparesis, Tropical Spastic; Postural Balance
PubMed: 31391511
DOI: 10.1038/s41598-019-47920-z -
Identification and tracking of HTLV-1-infected T cell clones in virus-associated neurologic disease.JCI Insight Apr 2023Human T lymphotropic virus type 1-assoicated (HTLV-1-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disease caused by the...
Human T lymphotropic virus type 1-assoicated (HTLV-1-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disease caused by the persistent proliferation of HTLV-1-infected T cells. Here, we performed a T cell receptor (TCR) repertoire analysis focused on HTLV-1-infected cells to identify and track the infected T cell clones that are preserved in patients with HAM/TSP and migrate to the CNS. TCRβ repertoire analysis revealed higher clonal expansion in HTLV-1-infected cells compared with noninfected cells from patients with HAM/TSP and asymptomatic carriers (ACs). TCR clonality in HTLV-1-infected cells was similar in patients with HAM/TSP and ACs. Longitudinal analysis showed that the TCR repertoire signature in HTLV-1-infected cells remained stable, and highly expanded infected clones were preserved within each patient with HAM/TSP over years. Expanded HTLV-1-infected clones revealed different distributions between cerebrospinal fluid (CSF) and peripheral blood and were enriched in the CSF of patients with HAM/TSP. Cluster analysis showed similarity in TCRβ sequences in HTLV-1-infected cells, suggesting that they proliferate after common antigen stimulation. Our results indicate that exploring TCR repertoires of HTLV-1-infected cells can elucidate individual clonal dynamics and identify potential pathogenic clones expanded in the CNS.
Topics: Humans; Human T-lymphotropic virus 1; T-Lymphocytes; Paraparesis, Tropical Spastic; Clone Cells; Receptors, Antigen, T-Cell
PubMed: 37036006
DOI: 10.1172/jci.insight.167422 -
Journal of Inherited Metabolic Disease Jan 2015Over one hundred diseases related to inherited defects of complex lipids synthesis and remodeling are now reported. Most of them were described within the last 5 years.... (Review)
Review
Over one hundred diseases related to inherited defects of complex lipids synthesis and remodeling are now reported. Most of them were described within the last 5 years. New descriptions and phenotypes are expanding rapidly. While the associated clinical phenotype is currently difficult to outline, with only a few patients identified, it appears that all organs and systems may be affected. The main clinical presentations can be divided into (1) Diseases affecting the central and peripheral nervous system. Complex lipid synthesis disorders produce prominent motor manifestations due to upper and/or lower motoneuron degeneration. Motor signs are often complex, associated with other neurological and extra-neurological signs. Three neurological phenotypes, spastic paraparesis, neurodegeneration with brain iron accumulation and peripheral neuropathies, deserve special attention. Many apparently well clinically defined syndromes are not distinct entities, but rather clusters on a continuous spectrum, like for the PNPLA6-associated diseases, extending from Boucher-Neuhauser syndrome via Gordon Holmes syndrome to spastic ataxia and pure hereditary spastic paraplegia; (2) Muscular/cardiac presentations; (3) Skin symptoms mostly represented by syndromic (neurocutaneous) and non syndromic ichthyosis; (4) Retinal dystrophies with syndromic and non syndromic retinitis pigmentosa, Leber congenital amaurosis, cone rod dystrophy, Stargardt disease; (5) Congenital bone dysplasia and segmental overgrowth disorders with congenital lipomatosis; (6) Liver presentations characterized mainly by transient neonatal cholestatic jaundice and non alcoholic liver steatosis with hypertriglyceridemia; and (7) Renal and immune presentations. Lipidomics and molecular functional studies could help to elucidate the mechanism(s) of dominant versus recessive inheritance observed for the same gene in a growing number of these disorders.
Topics: Ataxia; Bone Diseases, Developmental; Fatty Liver; Humans; Hypertriglyceridemia; Ichthyosis; Jaundice; Leber Congenital Amaurosis; Lipid Metabolism, Inborn Errors; Lipids; Lipomatosis; Liver Diseases; Macular Degeneration; Neurodegenerative Diseases; Paraparesis, Spastic; Peripheral Nervous System Diseases; Phenotype; Retinal Dystrophies; Retinitis Pigmentosa; Spastic Paraplegia, Hereditary; Stargardt Disease
PubMed: 25413954
DOI: 10.1007/s10545-014-9776-6 -
Annals of Clinical and Translational... Feb 2023HTLV-1 infection causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), resulting in loss of motor function. In this Phase 2 trial, we assessed the...
OBJECTIVE
HTLV-1 infection causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), resulting in loss of motor function. In this Phase 2 trial, we assessed the efficacy and safety of l-arginine in patients with HAM/TSP.
METHODS
This open-label, single-arm, Phase 2 study enrolled patients diagnosed with HAM/TSP. Patients received l-arginine at a dose of 20 g orally for 1 week and were followed-up for 3 weeks. The primary endpoint was change in walking speed in the 10-m walk test (10MWT). The main secondary endpoints were change in Timed Up and Go Test (TUGT) time, improvement in inflammatory markers in cerebrospinal fluid (CSF), safety, and tolerability.
RESULTS
The study enrolled 20 patients (13 [65%] female) with a mean age of 67.8 years (95% CI 62.3 to 73.3). Although the primary endpoint, the changes in 10MWT time between baseline (Day 0) and Day 7, did not reach statistical significance (mean percent change in time -3.5%, 95% CI -10.8% to 3.7%; P = 0.32), a significant improvement was detected between baseline and Day 14 (-9.4%, 95% CI -16.6% to -2.2%; P = 0.01). Significant improvements were also observed in selected secondary endpoints, including in TUGT time (-9.1%, 95% CI -15.5% to -2.7%; P < 0.01), and in neopterin concentration in CSF (-2.1 pmol/mL, 95% CI -3.8 to -0.5; P = 0.01). Adverse events were infrequent, mild, and resolved rapidly.
INTERPRETATION
l-arginine therapy improved motor function and decreased CSF inflammatory markers. l-arginine thus represents a promising therapeutic option for patients with HAM/TSP.
TRIAL REGISTRATION NUMBER
UMIN000023854.
Topics: Humans; Female; Aged; Male; Human T-lymphotropic virus 1; Postural Balance; Time and Motion Studies; Paraparesis, Tropical Spastic; HTLV-I Infections
PubMed: 36547017
DOI: 10.1002/acn3.51715 -
Journal of Vascular Surgery Jun 2016Transient and permanent paraparesis and paraplegia (spinal cord injury [SCI]) are reported in up to 13% of patients undergoing thoracic endovascular aortic repair...
OBJECTIVE
Transient and permanent paraparesis and paraplegia (spinal cord injury [SCI]) are reported in up to 13% of patients undergoing thoracic endovascular aortic repair (TEVAR) for descending thoracic aortic aneurysm, thoracoabdominal aortic aneurysm, and thoracic aortic dissection. We hypothesize that aggressive intraoperative and postoperative neuroprotective interventions prevent or significantly reduce all SCI in TEVAR.
METHODS
Using a prospectively maintained, Institutional Review Board-approved database, we retrospectively reviewed all TEVARs performed in a university tertiary referral center from 2005 to 2014 to study the incidence of all transient and permanent lower extremity SCI. Only TEVARs for traumatic aortic tear were excluded. Arch debranching and carotid subclavian bypass were performed before TEVAR in patients with arch involvement. All patients had moderate systemic hypothermia (34°C), mean arterial pressure ≥90 mm Hg, and hemoglobin ≥10 g/dL. Patients received mannitol (12.5 g), methylprednisolone (30 mg/kg), and naloxone (1 μg/kg/h). Patients in whom >12 cm of aortic coverage was planned had spinal fluid drained to a pressure of <8 mm Hg intraoperatively and postoperatively until normal leg strength was confirmed. The main outcome measure was transient or permanent SCI.
RESULTS
One hundred fifty-five patients had TEVAR between 2005 and 2014. Mean age was 74 years, and 56.1% were male. Descending thoracic aortic aneurysm was present in 91.6%, thoracoabdominal aortic aneurysm in 8.4%, and dissection in 28.8%. Presentation was acute in 42.5%. The procedure included carotid-subclavian bypass in 18.7% of patients. Seventy-two percent of patients had spinal fluid drainage. Mean aortic coverage was 25 cm. Eighty-one percent of patients had >12 cm aortic coverage, and 49% had complete coverage of the thoracic aorta (coverage from subclavian to celiac artery). In-hospital mortality was 1.94%. Stroke occurred in 1.32% of patients. No patient had renal failure. SCI occurred in 0.65% (1 of 154) of patients.
CONCLUSIONS
SCI in TEVAR can be significantly reduced by using proactive intraoperative and postoperative neuroprotective interventions that prolong spinal cord ischemic tolerance and increase spinal cord perfusion and oxygen delivery.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aortic Dissection; Aortic Aneurysm, Thoracic; Arterial Pressure; Blood Vessel Prosthesis Implantation; Child; Child, Preschool; Databases, Factual; Drainage; Endovascular Procedures; Female; Humans; Hypothermia, Induced; Infant; Infant, Newborn; Intraoperative Care; Male; Middle Aged; Monitoring, Physiologic; Paraparesis; Paraplegia; Postoperative Care; Regional Blood Flow; Retrospective Studies; Risk Factors; Spinal Cord Injuries; Spinal Cord Ischemia; Spinal Puncture; Time Factors; Treatment Outcome; Wisconsin; Young Adult
PubMed: 26968081
DOI: 10.1016/j.jvs.2015.12.062