Serum neurofilament-light and glial fibrillary acidic protein levels in hydroxychloroquine-treated primary progressive multiple sclerosis.

BACKGROUND: In a recent trial, hydroxychloroquine (HCQ) treatment reduced the expected rate of disability worsening at 18 months in primary progressive multiple sclerosis (PPMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in multiple sclerosis. METHODS: We measured NfL and GFAP levels in serum samples from 39 patients with inactive PPMS included in a phase II clinical trial of HCQ treatment in PPMS at multiple time points over 18 months, and investigated the association of these biomarkers with clinical disability at screening and during follow-up. Screening and 12-month retinal nerve fiber layer (RNFL) thickness was also recorded and analyzed. RESULTS: NfL and GFAP levels increased over time, but only significantly from screening to month 6. NfL and GFAP levels did not significantly increase from month 6 up to month 18. At screening, NfL and GFAP levels did not correlate with the Expanded Disability Status Scale (EDSS), and GFAP but not NfL modestly correlated with Timed 25-Foot Walk test (T25FW). Screening NfL and GFAP levels did not predict disability worsening (≥20% worsening on the T25FW) at month 18. RNFL thickness decreased significantly from screening to month 12 and independently predicted disability worsening. CONCLUSIONS: In this cohort of people with inactive PPMS, HCQ treatment attenuated the increase of NfL and GFAP after 6 months of treatment and up to 18 months of follow-up, suggesting a treatment effect of HCQ over these biomarkers. RNFL thickness, a marker of neuroaxonal atrophy, was associated with disability worsening, and should be explored further as a prognostic marker in this population.

Inner Retinal Layer Changes Reflect Changes in Ambulation Score in Patients with Primary Progressive Multiple Sclerosis.

The establishment of surrogate markers to detect disability progression in persons with multiple sclerosis (PwMS) is important to improve monitoring of clinical deterioration. Optical coherence tomography (OCT) could be such a tool. However, sufficient longitudinal data of retinal neuroaxonal degeneration as a marker of disease progression exist only for PwMS with a relapsing-remitting course (RRMS) so far. In contrast, longitudinal data of retinal layers in patients with primary-progressive MS (PPMS) are inconsistent, and the association of OCT parameters with ambulatory performance in PwMS has rarely been investigated. We aimed to investigate the relative annual rates of change in retinal layers in PwMS (RRMS and PPMS) compared with healthy controls (HC) using OCT and to evaluate their association with ambulatoryfunctionalscore (AS) worsening in PPMS. A retrospective analysis of a longitudinal OCT dataset of the retinal layers of PwMS and HC from two MS centers in Germany was performed. Walking ability was measured over a standardized distance of 500 m, and changes during the observation period were categorized using the AS and the expanded disability status scale (EDSS). 61 HC with 121 eyes and 119 PwMS (PPMS: 57 patients with 108 eyes; RRMS: 62 patients with 114 eyes) were included. The median follow-up time for PwMS was 3 years. The relative annual change of pRNFL (peripapillary retinal nerve fiber layer) and INL (inner nuclear layer) was significantly different in PwMS compared with HC. RRMS and PPMS subgroups did not differ in the annual atrophy rates. In patients with PPMS, worsening of the AS was significantly associated with increased thinning of the TMV (total macular volume), GCIP (ganglion cell and inner plexiform layer), and ONPL (outer nuclear and outer plexiform layer) (all p-value < 0.05, r > 0.30). For every -0.1% decrease in the TMV, GCIP, and ONPL, the risk of a deterioration in the AS increased by 31% (hazard ratio (HR): 1.309), 11% (HR: 1.112), and 16% (HR: 1.161), respectively. In addition, worsening EDSS in PPMS was significantly associated with the relative annual atrophy rates of pRNFL, TMV, and GCIP (all p-value < 0.05). Disability progression in PPMS can be measured using OCT, and increasing annual atrophy rates of the inner retinal layers are associated with worsening ambulation. OCT is a robust and side-effect-free imaging tool, making it suitable for routine monitoring of PwMS.

The Dual PDE7-GSK3ß Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune and degenerative disease with axonal damage and demyelination as its main features. Its dual neurological and autoimmune nature makes it a disease that is difficult to treat. Treatments that simultaneously stop the immune response while protecting and repairing the nervous system are urgent. That is of utmost importance for the primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS, characterized by worsening neurological function from the onset of symptoms. In this sense, inhibitors of glycogen synthase kinase 3ß (GSK3ß) and phosphodiesterase 7 (PDE7) have recently shown great therapeutic potential for the treatment of demyelinating diseases. Here we investigated a dual inhibitor of these two targets, the small molecule VP3.15, in a preclinical model, which resembles primary-progressive MS (PPMS), the Theiler's mouse encephalomyelitis virus-induced demyelinated disease (TMEV-IDD). In our study, VP3.15 ameliorates the disease course improving motor deficits of infected mice. Chronic treatment with VP3.15 also showed significant efficacy in the immunomodulation process, as well as in the proliferation and differentiation of oligodendroglial precursors, improving the preservation of myelin and axonal integrity. Therefore, our results support a treatment with the safe VP3.15 as an integrative therapeutic strategy for the treatment of PPMS.

Serum Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers in Primary Progressive Multiple Sclerosis and Hereditary Spastic Paraplegia Type 4.

In patients with slowly progressive spastic paraparesis, the differential diagnosis of primary progressive multiple sclerosis (PPMS) and hereditary spastic paraplegia (HSP) can be challenging. Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising fluid biomarkers to support the diagnostic workup. Serum NfL is a marker of neuroaxonal decay sensitive to temporal changes, while elevated sGFAP levels may reflect astrocytal involvement in PPMS. We assessed sNfL and sGFAP levels in 25 patients with PPMS, 25 patients with SPG4 (the most common type of HSP) and 60 controls, using the highly sensitive single-molecule array (Simoa) platform. Patients were matched in age, sex, age at onset, disease duration and disease severity. Serum NfL levels were significantly increased in PPMS compared to SPG4 (p = 0.041, partial η² = 0.088), and there was a trend toward relatively higher sGFAP levels in PPMS (p = 0.097). However, due to overlapping biomarker values in both groups, we did not find sNfL and sGFAP to be useful as differential biomarkers in our cohort. The temporal dynamics indicate sNfL and sGFAP levels are most markedly elevated in PPMS in earlier disease stages, supporting their investigation in this group most in need of a diagnostic biomarker.

Patient-reported outcomes are worse for progressive-onset multiple sclerosis than relapse-onset multiple sclerosis, particularly early in the disease process.

BACKGROUND AND PURPOSE: Treatments for progressive-onset multiple sclerosis (MS) are lacking. To improve the disease management for progressive-onset MS, the differences between relapse-onset MS and progressive-onset MS in patient-reported disability, progression and symptoms were examined. METHODS: A total of 1985 participants of the Australian Multiple Sclerosis Longitudinal Study were included. Associations between onset type and outcomes were assessed with negative binomial regression. RESULTS: The severity of 17 of the 19 outcomes was significantly higher for progressive-onset MS patients than relapse-onset MS patients, including perspectives from disability, progression over the last year, fatigue, sensory, walking difficulties, pain, balance, spasticity, sexual dysfunction, bladder, bowel, anxiety, depression and the European quality of life (EQ-5D) (P < 0.05; adjusted mean ratio ranged from 1.11 to 1.52). The differences between the two onset types were most pronounced early in the disease process and reduced with increasing MS duration, and the interaction was significant for disability, progression over the last year, walking difficulties, bladder problems, bowel problems and spasticity. CONCLUSION: Participants with progressive-onset MS were significantly worse off on nearly all patient-reported outcomes than relapse-onset MS participants, and the differences were most pronounced early in the disease course, highlighting the importance of early intervention for those with progressive-onset MS.

MOG-IgG in primary and secondary chronic progressive multiple sclerosis: a multicenter study of 200 patients and review of the literature.

BACKGROUND: Antibodies to human full-length myelin oligodendrocyte glycoprotein (MOG-IgG) as detected by new-generation cell-based assays have recently been described in patients presenting with acute demyelinating disease of the central nervous system, including patients previously diagnosed with multiple sclerosis (MS). However, only limited data are available on the relevance of MOG-IgG testing in patients with chronic progressive demyelinating disease. It is unclear if patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS) should routinely be tested for MOG-IgG. OBJECTIVE: To evaluate the frequency of MOG-IgG among patients classified as having PPMS or SPMS based on current diagnostic criteria. METHODS: For this purpose, we retrospectively tested serum samples of 200 patients with PPMS or SPMS for MOG-IgG using cell-based assays. In addition, we performed a review of the entire English language literature on MOG-IgG published between 2011 and 2017. RESULTS: None of 139 PPMS and 61 SPMS patients tested was positive for MOG-IgG. Based on a review of the literature, we identified 35 further MOG-IgG tests in patients with PPMS and 55 in patients with SPMS; the only reportedly positive sample was positive just at threshold level and was tested in a non-IgG-specific assay. In total, a single borderline positive result was observed among 290 tests. CONCLUSION: Our data suggest that MOG-IgG is absent or extremely rare among patients with PPMS or SPMS. Routine screening of patients with typical PPMS/SPMS for MOG-IgG seems not to be justified.

Circulating microRNAs as biomarkers in progressive multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), microRNA (miRNA) dysregulation is mostly reported in different immune cells, but less information is available on circulating miRNAs that exert strong biomarker potential due to their exceptional stability in body fluids. OBJECTIVE: The aim of this study was to profile expression of circulating miRNAs in primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS) and assess their association with neurological worsening. METHODS: The expressions of 84 different miRNAs were profiled in serum of 83 subjects (62 MS and 21 controls) using miScript miRNA techniques. First, they were screened on 18 PPMS and 10 controls; thereafter, 10 most aberrantly expressed miRNAs were validated on a larger cohort. RESULTS: In comparison with controls, upregulation of miR-191-5p was found in both progressive MS subtypes, while miR-376c-3p was overexpressed only in PPMS. Additionally, upregulation of miR-128-3p and miR-24-3p was detected in PPMS when compared to controls and SPMS. Progression index correlated with miR-128-3p in PPMS and miR-375 in SPMS. CONCLUSION: We detected overexpression of four miRNAs that have not been previously associated with progressive forms of MS. The increased expression of circulating miR-191-5p seems to be associated with progressive forms of MS, while miR-128-3p seems to be associated mostly with PPMS.

Reversible Fermi Level Tuning of a Sb2Te3 Topological Insulator by Structural Deformation.

For three-dimensional (3D) topological insulators that have a layered structure, strain was used to control critical physical properties. Here, we show that tensile strain decreases bulk carrier density while accentuating transport of topological surface state using temperature-dependent resistance and magneto-resistance measurements, terahertz-time domain spectroscopy and density functional theory calculations. The induced strain was confirmed by transmittance X-ray scattering measurements. The results show the possibility of reversible topological surface state device control using structural deformation.

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs.

Identical lesion morphology in primary progressive and relapsing-remitting MS--an ultrahigh field MRI study.

Potential differences between primary progressive (PP) and relapsing-remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g., perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI.

Composite end points to assess delay of disability progression by MS treatments.

BACKGROUND: The Expanded Disability Status Scale (EDSS) has low sensitivity and reliability for detecting sustained disability progression (SDP) in multiple sclerosis (MS) trials. OBJECTIVE: This study evaluated composite disability end points as alternatives to EDSS alone. METHODS: SDP rates were determined using 96-week data from the Olympus trial (rituximab in patients with primary progressive MS). SDP was analyzed using composite disability end points: SDP in EDSS, timed 25-foot walk test (T25FWT), or 9-hole peg test (9HPT) (composite A); SDP in T25FWT or 9HPT (composite B); SDP in EDSS and (T25FWT or 9HPT) (composite C); and SDP in any two (EDSS, T25FWT, and 9HPT) (composite D). RESULTS: Overall agreements between EDSS and other disability measures in defining SDP were 66%-73%. Composite A showed similar treatment effect estimate versus EDSS alone with much higher SDP rates. Composite B, C, and D all showed larger treatment effect estimate with different or similar SDP rates versus EDSS alone. Using composite A (24-week confirmation only), B, C, or D could reduce sample sizes needed for MS trials. CONCLUSION: Composite end points including multiple accepted disability measures could be superior to EDSS alone in analyzing disability progression and should be considered in future MS trials.

Utility of an untargeted metabolomics approach using a 2D GC-GC-MS platform to distinguish relapsing and progressive multiple sclerosis.

Introduction: Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease of the central nervous system (CNS) in young adults and results in progressive neurological defects. The relapsing-remitting phenotype (RRMS) is the most common disease course in MS and may progress to the progressive form (PPMS). Objectives: There is a gap in knowledge regarding whether the relapsing form can be distinguished from the progressive course or healthy subjects (HS) based on an altered serum metabolite profile. In this study, we performed global untargeted metabolomics with the 2D GCxGC-MS platform to identify altered metabolites between RRMS, PPMS, and HS. Methods: We profiled 235 metabolites in the serum of patients with RRMS (n=41), PPMS (n=31), and HS (n=91). A comparison of RRMS and HS patients revealed 22 significantly altered metabolites at p<0.05 (false discovery rate [FDR]=0.3). The PPMS and HS comparisons revealed 28 altered metabolites at p<0.05 (FDR=0.2). Results: Pathway analysis using MetaboAnalyst revealed enrichment of four metabolic pathways in both RRMS and PPMS (hypergeometric test p<0.05): 1) galactose metabolism; 2) amino sugar and nucleotide sugar metabolism; 3) phenylalanine, tyrosine, and tryptophan biosynthesis; and 4) aminoacyl-tRNA biosynthesis. The Qiagen IPA enrichment test identified the sulfatase 2 (SULF2) (p=0.0033) and integrin subunit beta 1 binding protein 1 (ITGB1BP1) (p=0.0067) genes as upstream regulators of altered metabolites in the RRMS vs. HS groups. However, in the PPMS vs. HS comparison, valine was enriched in the neurodegeneration of brain cells (p=0.05), and heptadecanoic acid, alpha-ketoisocaproic acid, and glycerol participated in inflammation in the CNS (p=0.03). Conclusion: Overall, our study suggested that RRMS and PPMS may contribute metabolic fingerprints in the form of unique altered metabolites for discriminating MS disease from HS, with the potential for constructing a metabolite panel for progressive autoimmune diseases such as MS.

Primary pulmonary myxoid sarcoma with EWSR1::CREB1 fusion: a literature review.

PURPOSE: This review primarily aims to review the epidemiology, clinical characteristics, imaging, pathology, immunohistochemistry, diagnosis, differential diagnosis, treatment, and prognosis of Primary pulmonary myxoid sarcoma (PPMS) with EWS RNA binding protein 1::cAMP response element binding protein 1 (EWSR1::CREB1) fusion. It provides reference for the diagnosis and treatment of this disease. METHODS: Retrospectively collected the literature about PPMS with EWSR1::CREB1 fusion, its clinical, radiology, histology, molecular characteristics and current treatment strategies were collated and analyzed. This review provides a detailed differential diagnosis of the disease. RESULTS: PPMS is an exceptionally rare, low-grade malignant tumor of the lung. This tumor commonly infiltrates lung tissue and develops within bronchial passages. It is identified by a genetic rearrangement involving the EWSR1 gene and a distinct chromosomal translocation t(2; 22)(q33; q12). Variants include EWSR1::CREB1 fusion and EWS RNA binding protein 1::activating transcription factors (EWSR1::ATF1) fusion. PPMS with EWSR1::CREB1 fusion is more prevalent among middle-aged individuals and affects both sexes almost equally. Clinical symptoms are relatively non-specific, primarily including cough, hemoptysis, and weight loss. Most patients undergo surgery and experience a favorable prognosis. Further research is required to validate the effectiveness of alternative treatments for PPMS with EWSR1::CREB1 fusion. CONCLUSION: EWSR1 rearrangement and EWSR1::CREB1 fusion are crucial genetic features of PPMS and serve as important diagnostic markers. Immunohistochemically, PPMS tests positive for EMA. In terms of treatment, surgery has been the primary approach in recent years. Therefore, the efficacy of other treatments still requires further investigation.

Biomarkers of disability worsening in inactive primary progressive multiple sclerosis.

OBJECTIVE: To investigate serum biomarkers of progression in inactive primary progressive multiple sclerosis (PPMS). METHODS: We measured protein biomarkers (growth differentiation factor-15 (GDF-15), dickkopf-1 (DKK-1), neuron specific enolase (NSE) and cathepsin-D) in serum samples from 39 patients with inactive PPMS included in a clinical trial enrolling people with PPMS (clinicaltrials.gov identifier NCT02913157) and investigated the association of these biomarker levels with clinical disability at baseline and during follow-up. We then performed a meta-analysis of publicly available transcriptomic datasets to investigate the gene expression of these biomarkers in the CNS in progressive MS. RESULTS: When compared with healthy controls, people with PPMS had higher serum levels of GDF-15, DKK-1 and cathepsin-D at baseline. These findings match those in our meta-analysis which found increased expression of GDF-15 and cathepsin-D in the CNS in progressive MS. At baseline, elevated serum DKK-1 was associated with worse Expanded Disability Status Scale (EDSS) and nine-hole peg test (9HPT) scores. None of the other biomarkers levels significantly correlated with EDSS, Timed 25-Foot Walk Test (T25FWT), 9HPT, or cognitive measures. However, serum GDF-15 and cathepsin-D were higher at baseline in participants who developed worsening disability. Our receiver operating characteristic curve showed that higher serum GDF-15 and cathepsin-D at baseline significantly discriminated between participants who worsened in T25FWT and 9HPT and those who remained stable. CONCLUSIONS: Patients with PPMS have altered levels of GDF-15, DKK-1 and cathepsin-D in serum, and GDF-15 and cathepsin-D may have predictive value in progression free of inflammatory activity in PPMS.

Treated and Untreated Primary Progressive Multiple Sclerosis: Walkthrough Immunological Changes of Monocytes and T Regulatory Cells.

The objective of this study was to investigate regulatory T cells (Tregs) and monocytes; specifically, the expression of CTLA-4 (CD152) and FOXP3+ in CD4+CD25+ Tregs and the expression of CD40+ and CD192+ monocyte subpopulations in subjects with primary progressive multiple sclerosis (PPMS). Immunological analysis was conducted on peripheral blood samples collected from the 28 PPMS subjects (15 treated with ocrelizumab and 13 untreated PPMS subjects) and 10 healthy control subjects (HCs). The blood samples were incubated with antihuman CD14, CD16, CD40, and CD192 antibodies for monocytes and antihuman CD4, CD25, FOXP3, and CTLA-4 antibodies for lymphocytes. The study results showed that in comparison to HCs both ocrelizumab treated (N = 15) and untreated (N = 13) PPMS subjects had significantly increased percentages of CTLA-4+ and FOXP3+ in CD4+CD25+ Tregs. Further, ocrelizumab treated PPMS subjects, compared to the untreated ones, had significantly decreased percentages of CD192+ and CD40+ nonclassical monocytes. Increased percentages of CTLA-4+ and FOXP3+ in CD4+CD25+ Tregs in both ocrelizumab treated and untreated PPMS subjects indicates the suppressive (inhibitory) role of Tregs in abnormal immune responses in PPMS subjects. Decreased percentages of CD40+ and CD192+ non-classical CD14+CD16++ monocytes for treated compared to untreated PPMS subjects suggests a possible role for ocrelizumab in dampening CNS inflammation.

EDSS variability before randomization may limit treatment discovery in primary progressive MS.

BACKGROUND: Baseline Expanded Disability Status Scale (EDSS) is usually based on a single measurement. Here we evaluated whether using a baseline EDSS derived from two pre-treatment measurements improves the detection of progression events and the ability to demonstrate a therapeutic effect in delaying MS disability progression. METHODS: Real data from OLYMPUS, a phase II/III randomized, placebo-controlled trial of rituximab in patients with primary progressive multiple sclerosis (PPMS), as well as simulated data were analyzed. Several definitions of baseline EDSS were used to capture sustained disability progression (SDP) events. Variations in the EDSS were estimated by linear mixed-effect models. RESULTS: Selecting the higher of two baseline EDSS scores lowered the number of SDP events in both treatment groups, so decreasing sensitivity, and reduced the number of false SDP events, so increasing specificity. Conversely, selecting the lower of two baseline scores increased sensitivity but decreased specificity. Increased power (~7% based on the simulation study) was observed when the average of screening and Week 0 EDSS scores was used for baseline. CONCLUSION: Baseline EDSS derived from two pre-treatment EDSS measurements may enhance the ability of detecting a therapeutic effect in slowing disability progression in PPMS. This strategy could be implemented in future clinical trials of patients with MS.

Cognitive reserve and symptom experience in multiple sclerosis: a buffer to disability progression over time?

OBJECTIVE: To investigate the possible buffering effect of cognitive reserve on symptom experience for multiple sclerosis (MS) disease course. DESIGN: Secondary analysis of longitudinal data from the North American Research Committee on MS Registry. SETTING: Registry study and web-based supplemental survey. PARTICIPANTS: People with MS (N=859). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Two health outcome measures, the Symptom Inventory and the Performance Scales, were collected biannually over 1 and 6 years, respectively. Active and passive cognitive reserve was measured using the Stern Leisure Activities and the Sole-Padulles Childhood Enrichment tools, respectively. Linear regression, chi-square, multilevel random-effects modeling, and classification and regression tree modeling were used to compare cross-sectional means, disease course by cognitive reserve, longitudinal trajectories, and active cognitive reserve item endorsement by disability groups, respectively. RESULTS: Patients with high-active reserve had a lesser symptom burden than those with low-active reserve independent of passive reserve (P<.01). Cognitive reserve was associated with course of disease, such that high-active patients were overrepresented among relapsing-remitting patients, and underrepresented among patients with progressive disease (χ(2)=14.7, P<.03). Longitudinal modeling revealed a significant interaction of active reserve and time in mobility, fatigue, and overall disability in the whole sample (P<.05 in all comparisons). Among patients whose disability trajectories changed over time, active cognitive reserve was associated with less deterioration (P<.001). Passive cognitive reserve evidenced no effect in the longitudinal analyses. Active cognitive reserve scores across disability groups had a similar range but comprised different items, indicating that patients maintain active cognitive reserve with different activities as the disease progresses. CONCLUSIONS: Our findings suggest that active cognitive reserve is a buffer for functional limitation across disability groupings. Cognitive reserve may provide an alternative lens for thinking about the disease course of MS, providing a longer "runway" until disability accrual through cortical remodeling. Loss of cognitive reserve may explain the onset of progressive disease in MS.

Higher frequency of Human herpesvirus-6 (HHV-6) viral DNA simultaneously with low frequency of Epstein-Barr virus (EBV) viral DNA in a cohort of multiple sclerosis patients from Rio de Janeiro, Brazil.

Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease of the central nervous system (CNS). The etiology of MS is not well understood, but it's likely one of the genetic and environmental factors. Approximately 85% of patients have relapsing-remitting MS (RRMS), while 10-15% have primary progressive MS (PPMS). Epstein-Barr virus (EBV) and Human herpesvirus 6 (HHV-6), members of the human Herpesviridae family, are strong candidates for representing the macroenvironmental factors associated with MS) pathogenesis. Antigenic mimicry of EBV involving B-cells has been implicate in MS risk factors and concomitance of EBV and HHV-6 latent infection has been associated to inflammatory MS cascade. To verify the possible role of EBV and HHV-6 as triggering or aggravating factors in RRMS and PPMS, we compare their frequency in blood samples collected from 166 MS patients. The presence of herpes DNA was searched by real-time PCR (qPCR). The frequency of EBV and HHV-6 in MS patients were 1.8% (3/166) and 8.9% (14/166), respectively. Among the positive patients, 100% (3/3) EBV and 85.8% (12/14) HHV-6 are RRMS and 14.4% (2/14) HHV-6 are PPMS. Detection of EBV was 1.2% (2/166) and HHV-6 was 0.6% (1/166) in blood donors. About clinical phenotype of these patients, incomplete multifocal myelitis, and optic neuritis were the main CNS manifestations. These are the first data about concomitant infection of these viruses in MS patients from Brazil. Up to date, our findings confirm a higher prevalence in female with MS and a high frequency of EBV and HHV-6 in RRMS patients.

Magnetic Analysis of MgFe Hydrotalcites as Powder and Dispersed in Thin Films within a Keratin Matrix.

Hydrotalcites (HTlcs) are a class of nanostructured layered materials that may be employed in a variety of applications, from green to bio technologies. In this paper, we report an investigation on HTlcs made of Mg and Fe, recently employed to improve the growth in vitro of osteoblasts within a keratin sponge. We carried out an analysis of powder materials and of HTlcs dispersed in keratin and spin-coated on a Si/SiO2 substrate at different temperatures. A magnetic study of the powders was carried out with a Quantum Design Physical Property Measurement System equipped with a Vibrating Sample Magnetometer. The data gathered prove that these HTlcs are fully paramagnetic, and keratin showed a very small magnetic response. Optical and Atomic Force Microscopy analyses of the thin films provide a detailed picture of clusters randomly dispersed in the films with various dimensions. The magnetic properties of these films were characterized using the Nano Magneto Optical Kerr Effect (NanoMOKE) down to 7.5 K. The data collected show that the local magnetic properties can be mapped with a micrometric resolution distinguishing HTlc regions from keratin ones. This approach opens new perspectives in the characterization of these composite materials.

The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone-Induced Model of Demyelination Simulating Progressive Multiple Sclerosis.

Progressive multiple sclerosis (MS) is a chronic disease with a unique pattern, which is histologically classified into the subpial type 3 lesions in the autopsy. The lesion is also homologous to that of cuprizone (CPZ) toxin-induced animal models of demyelination. Aberration of the tryptophan (TRP)-kynurenine (KYN) metabolic system has been observed in patients with MS; nevertheless, the KYN metabolite profile of progressive MS remains inconclusive. In this study, C57Bl/6J male mice were treated with 0.2% CPZ toxin for 5 weeks and then underwent 4 weeks of recovery. We measured the levels of serotonin, TRP, and KYN metabolites in the plasma and the brain samples of mice at weeks 1, 3, and 5 of demyelination, and at weeks 7 and 9 of remyelination periods by ultra-high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) after body weight measurement and immunohistochemical analysis to confirm the development of demyelination. The UHPLC-MS/MS measurements demonstrated a significant reduction of kynurenic acid, 3-hydoxykynurenine (3-HK), and xanthurenic acid in the plasma and a significant reduction of 3-HK, and anthranilic acid in the brain samples at week 5. Here, we show the profile of KYN metabolites in the CPZ-induced mouse model of demyelination. Thus, the KYN metabolite profile potentially serves as a biomarker of progressive MS and thus opens a new path toward planning personalized treatment, which is frequently obscured with immunologic components in MS deterioration.