Generation of a Sleeping Beauty Transposon-Based Cellular System for Rapid and Sensitive Screening for Compounds and Cellular Factors Limiting SARS-CoV-2 Replication.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the acute respiratory disease COVID-19, which has become a global concern due to its rapid spread. The common methods to monitor and quantitate SARS-CoV-2 infectivity in cell culture are so far time-consuming and labor-intensive. Using the Sleeping Beauty transposase system, we generated a robust and versatile cellular infection model that allows SARS-CoV-2 infection experiments compatible for high-throughput and live cell imaging.

Longitudinal Assessment of Multiple Sclerosis with the Brain-Age Paradigm.

Objective: During the natural course of multiple sclerosis (MS), the brain is exposed to aging as well as disease effects. Brain aging can be modeled statistically; the so-called "brain-age" paradigm. Here, we evaluated whether brain-predicted age difference (brain-PAD) was sensitive to the presence of MS, clinical progression, and future outcomes.

Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [F]GE-180: a Blocking Study Using XBD173 in Multiple Sclerosis Normal Appearing White and Grey Matter.

Purpose: Measurements of non-displaceable binding (V) of positron emission tomography (PET) ligands are not often made in vivo in humans because they require ligands to displace binding to target receptors and there are few readily available, safe ones to use. A technique to measure V for ligands for the 18-kDa translocator protein (TSPO) has recently been developed which compares the total volume of distribution (V) before and after administration of the TSPO ligand XBD173. Here, we used XBD173 with an occupancy plot to quantify V for two TSPO radiotracers, [F]GE-180 and [C]PBR28, in cohorts of people with multiple sclerosis (MS).

Over three decades study populations in progressive multiple sclerosis have become older and more disabled, but have lower on-trial progression rates: A systematic review and meta-analysis of 43 randomised placebo-controlled trials.

Background: Progression is the major driver of disability and cost in multiple sclerosis (MS). However, the search for treatments in progressive multiple sclerosis (PMS) has not mirrored the success in relapsing MS.

Objectives: To assess changes in PMS trials over time.

Neurofilament light as an immune target for pathogenic antibodies.

Antibodies to neuronal antigens are associated with many neurological diseases including paraneoplastic neurological disorders, epilepsy, amyotrophic lateral sclerosis and multiple sclerosis. Immunization with neuronal antigens such as neurofilament light (NF-L), a neuronal intermediate filament in axons, has been shown to induce neurological disease and spasticity in mice. Also, although antibodies to NF-L are widely used as surrogate biomarkers of axonal injury in amyotrophic lateral sclerosis and multiple sclerosis, it remains to be elucidated if antibodies to NF-L contribute to neurodegeneration and neurological disease.

Patient-reported outcomes and survival in multiple sclerosis: A 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29.

Background: There is increasing emphasis on using patient-reported outcomes (PROs) to complement traditional clinical outcomes in medical research, including in multiple sclerosis (MS). Research, particularly in oncology and heart failure, has shown that PROs can be prognostic of hard clinical endpoints such as survival time (time from study entry until death). However, unlike in oncology or cardiology, it is unknown whether PROs are associated with survival time in neurological diseases.

Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis.

It is well recognised that the majority of the impact of multiple sclerosis (MS), both personal and societal, arises in the progressive phase where disability accumulates inexorably. As such, progressive MS (PMS) has been the target of pharmacological therapies for many years. However, there are no current licensed treatments for PMS.

Iron overload and altered iron metabolism in ovarian cancer.

Iron is an essential element required for many processes within the cell. Dysregulation in iron homeostasis due to iron overload is detrimental. This nutrient is postulated to contribute to the initiation of cancer; however, the mechanisms by which this occurs remain unclear.

Inflammatory Activity on Natalizumab Predicts Short-Term but Not Long-Term Disability in Multiple Sclerosis.

Background: In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict a poor prognosis.

Objective: To study this association in those receiving natalizumab.

Methods: Data were collected on relapses, new MRI activity, and Modified Rio Score after initiation of natalizumab in an observational cohort of 161 patients with high baseline disability.

Progressive Dwindling in Multiple Sclerosis: An Opportunity to Improve Care.

Introduction: In the general ageing population, 40% of deaths occur following a prolonged trajectory of "progressive dwindling," characterised by chronic accumulation of disability and frailty, and associated with increased dependency and reduced reserves. Those who progressively dwindle are poorly catered for by current healthcare systems and would benefit from a coordinated approach to their medical and social care, known as formative care. People with multiple sclerosis (pwMS) may be more likely to progressively dwindle, and may be appropriate targets for formative care pathways.

Kinetic analysis of the translocator protein positron emission tomography ligand [F]GE-180 in the human brain.

Purpose: PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [C]PK-11195 limits accurate quantification. [F]GE-180, a novel TSPO ligand, displays superior binding to [C]PK-11195 in vitro.

Anti-JC virus antibody titres increase over time with natalizumab treatment.

Background: Anti-JC virus antibody status is a risk factor for progressive multifocal leukoencephalopathy after natalizumab treatment in multiple sclerosis. Previous studies have used a cross-sectional approach to conclude that the presence and duration of natalizumab treatment does not influence anti-JCV Ab seropositivity.

Objectives: Using a longitudinal approach, we measured change in anti-JCV Ab results after natalizumab treatment.

Multiple sclerosis therapy and Epstein-Barr virus antibody titres.

Background: Anti-Epstein-Barr virus (EBV) nuclear antigen-1 (anti-EBNA-1) IgG antibody titres have been found to correlate with MRI and clinical measures of disease activity in MS. Despite being a putative biomarker of disease activity, the effect of disease modifying drugs on anti-EBNA-1 IgG titre has not yet been determined.

Methods: In this study, we investigated the effect of interferon-beta and natalizumab therapy on prospective sera anti-EBNA-1 IgG titres, using a quantitative ELISA, in patients with relapsing-remitting MS.

Neurofilament light antibodies in serum reflect response to natalizumab treatment in multiple sclerosis.

Background: Increased levels of antibodies to neurofilament light protein (NF-L) in biological fluids have been found to reflect neuroinflammatory responses and neurodegeneration in multiple sclerosis (MS).

Objective: To evaluate whether levels of serum antibodies against NF-L correlate with clinical variants and treatment response in MS.

Methods: The autoantibody reactivity to NF-L protein was tested in serum samples from patients with relapsing-remitting MS (RRMS) (n=22) and secondary progressive MS (SPMS) (n=26).

Assessing dalfampridine efficacy in the physician's office.

Dalfampridine (extended release 4-aminopyridine) is shown in three recent randomised controlled trials to improve walking speed in people with multiple sclerosis; however, the trial literature makes it clear that dalfampridine is effective in only a subset of patients. For the neurologist working in an everyday physician's office, a key question arises: How to distinguish the few who experience a meaningful clinical benefit, from the many who do not? This question has not yet been adequately addressed in the available literature.

Vitamin B(12) deficiency with bilateral globus pallidus abnormalities.

Objective: To describe a case of vitamin B(12) deficiency with classic and rare clinical features and novel radiographic features.

Design: Case report.

Setting: Johns Hopkins Hospital neurology service.

Induction and expression of GluA1 (GluR-A)-independent LTP in the hippocampus.

Long-term potentiation (LTP) at hippocampal CA3-CA1 synapses is thought to be mediated, at least in part, by an increase in the postsynaptic surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors induced by N-methyl-d-aspartate (NMDA) receptor activation. While this process was originally attributed to the regulated synaptic insertion of GluA1 (GluR-A) subunit-containing AMPA receptors, recent evidence suggests that regulated synaptic trafficking of GluA2 subunits might also contribute to one or several phases of potentiation. However, it has so far been difficult to separate these two mechanisms experimentally.

Increased expression of thioredoxin-1 in human colorectal cancer is associated with decreased patient survival.

Thioredoxin-1 is a redox protein that, when overexpressed, causes increased cancer-cell growth and inhibited apoptosis. Thioredoxin-1 expression has been reported to be increased in several human primary tumors, but its relationship to tumor progression and patient survival has not been established. We studied the expression of thioredoxin-1 as measured with immunohistochemical staining in paraffin-embedded human normal colonic mucosa, adenomatous polyps, and primary and metastatic colorectal cancer.

Painless urethral bleeding: an unusual presentation of Von Willebrand disease.

Von Willebrand disease (vWD) is the most common bleeding disorder, and usually presents with either easy bruising or mucus membrane bleeding. Many patients are also diagnosed as a result of abnormal pre-operative laboratory tests. In this report, we describe two patients presenting with painless, persistent urethral bleeding as their initial manifestation of vWD.