Changes in serum neurofilament light chain levels following narrowband ultraviolet B phototherapy in clinically isolated syndrome.

OBJECTIVE: To determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB-PT). METHODS: sNfL levels were measured using a sensitive single-molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB-PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes. RESULTS: Baseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7-161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2-212.2) than in HC (10.7 pg/ml [IQR] 4.9-21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB-PT in the first 3 months (UVB-PT -10.6% vs non-UVB-PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall. CONCLUSIONS: Our findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro-axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB-PT.

Short-term changes in frequencies of circulating leukocytes associated with narrowband UVB phototherapy in people with clinically isolated syndrome.

Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). Low environmental exposure to UV radiation is implicated in risk of developing MS, and therefore, narrowband UVB phototherapy might delay progression to MS in people with CIS. Twenty individuals with CIS were recruited, and half were randomised to receive 24 sessions of narrowband UVB phototherapy over a period of 8 weeks. Here, the effects of narrowband UVB phototherapy on the frequencies of circulating immune cells and immunoglobulin levels after phototherapy are reported. Peripheral blood samples for all participants were collected at baseline, and 1, 2, 3, 6 and 12 months after enrolment. An extensive panel of leukocyte populations, including subsets of T cells, B cells, monocytes, dendritic cells, and natural killer cells were examined in phototherapy-treated and control participants, and immunoglobulin levels measured in serum. There were significant short-term increases in the frequency of naïve B cells, intermediate monocytes, and fraction III FoxP3+ T regulatory cells, and decreases in switched memory B cells and classical monocytes in phototherapy-treated individuals. Since B cells are increasingly targeted by MS therapies, the effects of narrowband UVB phototherapy in people with MS should be investigated further.

Identifying Patient-Specific Epstein-Barr Nuclear Antigen-1 Genetic Variation and Potential Autoreactive Targets Relevant to Multiple Sclerosis Pathogenesis.

BACKGROUND: Epstein-Barr virus (EBV) infection represents a major environmental risk factor for multiple sclerosis (MS), with evidence of selective expansion of Epstein-Barr Nuclear Antigen-1 (EBNA1)-specific CD4+ T cells that cross-recognize MS-associated myelin antigens in MS patients. HLA-DRB1*15-restricted antigen presentation also appears to determine susceptibility given its role as a dominant risk allele. In this study, we have utilised standard and next-generation sequencing techniques to investigate EBNA-1 sequence variation and its relationship to HLA-DR15 binding affinity, as well as examining potential cross-reactive immune targets within the central nervous system proteome. METHODS: Sanger sequencing was performed on DNA isolated from peripheral blood samples from 73 Western Australian MS cases, without requirement for primary culture, with additional FLX 454 Roche sequencing in 23 samples to identify low-frequency variants. Patient-derived viral sequences were used to predict HLA-DRB1*1501 epitopes (NetMHCII, NetMHCIIpan) and candidates were evaluated for cross recognition with human brain proteins. RESULTS: EBNA-1 sequence variation was limited, with no evidence of multiple viral strains and only low levels of variation identified by FLX technology (8.3% nucleotide positions at a 1% cut-off). In silico epitope mapping revealed two known HLA-DRB1*1501-restricted epitopes ('AEG': aa 481-496 and 'MVF': aa 562-577), and two putative epitopes between positions 502-543. We identified potential cross-reactive targets involving a number of major myelin antigens including experimentally confirmed HLA-DRB1*15-restricted epitopes as well as novel candidate antigens within myelin and paranodal assembly proteins that may be relevant to MS pathogenesis. CONCLUSIONS: This study demonstrates the feasibility of obtaining autologous EBNA-1 sequences directly from buffy coat samples, and confirms divergence of these sequences from standard laboratory strains. This approach has identified a number of immunogenic regions of EBNA-1 as well as known and novel targets for autoreactive HLA-DRB1*15-restricted T cells within the central nervous system that could arise as a result of cross-reactivity with EBNA-1-specific immune responses.

Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment.

We report a case of asymptomatic progressive multifocal leukoencephalopathy (PML) detected on regular MRI screening in a 40-year-old patient with subsequent benign course with 12 months follow-up. The patient had a history of aggressive inflammatory multiple sclerosis, prior mitoxantrone therapy, Stratify John Cunningham Virus test positivity (Quest Diagnostics, Madison, NJ, USA), and 5 years of natalizumab monotherapy. The initial MRI detection of PML was both atypical and subtle. Early diagnosis and intervention, and pre-emptive treatment for immune reconstitution inflammatory syndrome with high dose steroids, as well as empirical mirtazapine and mefloquine, were associated with a benign PML disease course and outcome.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 2 new and emerging therapies and their efficacy. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of ß-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 3 treatment practicalities and recommendations. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high.

Thermoresponsive substrates used for the expansion of human mesenchymal stem cells and the preservation of immunophenotype.

The facile regeneration of undifferentiated human mesenchymal stem cells (hMSCs) from thermoresponsive surfaces facilitates the collection of stem cells avoiding the use of animal derived cell detachment agents commonly used in cell culture. This communication proposes a procedure to fabricate coatings from commercially available pNIPAm which is both affordable and a significant simplification on alternative approaches used elsewhere. Solvent casting was used to produce films in the micrometer range and successful cell adhesion and proliferation was highly dependent on the thickness of the coating produced with 1 µm thick coatings supporting cells to confluence. 3T3 cell sheets and hMSCs were successfully detached from the cast coatings upon temperature reduction. Furthermore, results indicate that the hMSCs remained undifferentiated as the surface receptor profile of hMSCs was not altered when cells were detached in this manner.

Hypothalamic lesions in multiple sclerosis.

OBJECTIVES: To determine the frequency of hypothalamic lesions in patients with multiple sclerosis (MS) using conventional MRI (cMRI) protocols. METHODS: Brain cMRI (1.5 Tesla) scans of 105 Caucasian patients with classical MS (50 with stable and 55 with more active disease) and 12 patients with longitudinal extensive myelopathy (LEM) were reviewed retrospectively. NMO-IgG antibody was assayed in patients with hypothalamic lesions. RESULTS: Hypothalamic lesions were found in 13.3% of MS patients and in none of the LEM patients. A higher frequency of hypothalamic lesions was found in patients with active MS (18.2%) than in the stable group (8.0%), but this did not reach statistical significance (p=0.13). Patients with hypothalamic lesions also had more lesions in other cerebral structures. None of the LEM patients had hypothalamic lesions. No patients with hypothalamic lesions were positive for NMO-IgG. CONCLUSIONS: Hypothalamic lesions in MS are more frequent than previously reported and are not associated with NMO-IgG antibody.

A platinum-chromium steel for cardiovascular stents.

The desire to reduce the strut thickness of cardiovascular stents has driven the development of a new high strength radiopaque alloy, based on additions of platinum to a chromium-rich iron based matrix. This paper reports on initial development of the alloy and the rationale for selection of the composition. Data is presented for tensile and microstructural characterization, surface oxide analysis, corrosion resistance and endothelial cell response of the alloy. The results demonstrate the solid solution strengthening effect of the platinum, with an average yield strength of 480 MPa achieved. The material surface consists of primarily chromium oxide which contributes to the high corrosion resistance observed. The cell assay result suggests that surfaces of this Pt-enhanced alloy endothelialize in a manner comparable to stainless steel.