Coincident onset of multiple sclerosis and herpes simplex virus 1 encephalitis. a case report

Background: Along with vitamin D, smoking, body mass index and others, Epstein Barr virus, other herpesviruses and human endogenous retroviruses represent plausible environmental risk factors for multiple sclerosis. However, it is difficult to obtain direct proof of their involvement in the etiology of this condition. Case presentation: In order to contribute further evidence of the importance of these viruses, and speculate about disease-relevant interactions between these agents and a predisposed genetic background of the host, we describe the temporal association between multiple sclerosis onset and Herpes simplex 1-encephalitis in a female patient. Conclusions: This case illustrates a possible relationship between HSV-1 encephalitis and multiple sclerosis. Bearing in mind that association does not imply causation, some speculations about the etiology and pathophysiology of the two diseases can be made. The hypothesis of a genetic background predisposing to HSV-1 encephalitis and to immune-mediated demyelination is supported by the coincidence of the two conditions in this patient, along with data from animal models and genetic studies

Noise in multiple sclerosis: unwanted and necessary

As our knowledge about the etiology of multiple sclerosis (MS) increases, deterministic paradigms appear insufficient to describe the pathogenesis of the disease, and the impression is that stochastic phenomena (i.e. random events not necessarily resulting in disease in all individuals) may contribute to the development of MS. However, sources and mechanisms of stochastic behavior have not been investigated and there is no proposed framework to incorporate nondeterministic processes into disease biology. In this report, we will first describe analogies between physics of nonlinear systems and cell biology, showing how small-scale random perturbations can impact on large-scale phenomena, including cell function. We will then review growing and solid evidence showing that stochastic gene expression (or gene expression “noise”) can be a driver of phenotypic variation. Moreover, we will describe new methods that open unprecedented opportunities for the study of such phenomena in patients and the impact of this information on our understanding of MS course and therapy

Leptomeningitis in a person with radiologically isolated syndrome and latent tuberculosis. A case report with implications for clinical research

A 39-year-old man, followed with serial MRI of CNS for a radiologically isolate syndrome (RIS, a recently described condition considered a subclinical form of MS), was hospitalized for the occurrence of a leptomeningitis. Routine blood tests and contrast enhanced total body CT scan were unremarkable. Cerebrospinal fluid (CSF) examination showed increase of cells (22 mononuclear cells/mm3), albumin (294 mg/L), immunoglobilins G (161 mg/L) and Link Index (1.9), with 17 oligoclonal bands. Microbiological examinations of CSF (including those for Koch’s Bacillus) were negative. The Mantoux reaction and the QuantiFERON test were positive, featuring a latent tuberculosis (TB). The patient started prophylaxis with rifampicin and isoniazid for four months, until a new MRI showed the disappearance of the leptomeningeal enhancement, and the stability of white matter brain and spinal cord lesions. Two other MRI scans showed a new brain Gd-enhancing lesion nine month after anti-tubercular therapy and, after additional six months, new cerebral and spinal cord areas. This case provides the following suggestions about the effects of TB infection and related therapies on the underlying autoimmune status: the infection, while actively present, did not exacerbate the RIS condition; the worsening nine months after the prophylaxis discontinuation might have been the ‘natural’ evolution of RIS condition. Alternative speculative hypotheses include a remote effect of the infection, of isoniazid (that was reported in some cases to trigger MS), or the result of the clearance of the infection itself. Irrespective of the existence of any interaction between RIS and TB infection, It seems important to collect cases with MS-related diseases and concomitant infections, that may provide clues about disease pathogenesis and treatment

I Lamenti d''Orfeo

Am 4. April, dem Karfreitag des Jahres 1749, an dem am Dresdner Hof keine Opernaufführung stattfinden konnte, kam I Lamenti d’Orfeo, Festa di Camera consagrata alle Glorie Auguste di Ermelinda Talea. Patrocinio, e Decoro d’Arcadia, Poesia del Sig.re Ab:te Giov. Claudio Pasquini d:to Trigenio Migonitidio Pastore Arcade. Musica di Giov. Alberto Ristori 1749 zur Aufführung. Mitwirkende waren Calliope, eine Muse: Rosa Ravona, Orfeo, ihr Sohn: Regina Mingotti. Vermutlich hat Ristori die Hofkapelle vom Cembalo aus geleitet

I Lamenti d’Orfeo: Festa di camera für 2 Soprane, 2 Hörner, 2 Flöten, 2 Oboen, 2 Fagotte, 2 Violinen, Viola und Basso continuo: Partitur

Am 4. April, dem Karfreitag des Jahres 1749, an dem am Dresdner Hof keine Opernaufführung stattfinden konnte, kam I Lamenti d’Orfeo, Festa di Camera consagrata alle Glorie Auguste di Ermelinda Talea. Patrocinio, e Decoro d’Arcadia, Poesia del Sig.re Ab:te Giov. Claudio Pasquini d:to Trigenio Migonitidio Pastore Arcade. Musica di Giov. Alberto Ristori 1749 zur Aufführung. Mitwirkende waren Calliope, eine Muse: Rosa Ravona, Orfeo, ihr Sohn: Regina Mingotti. Vermutlich hat Ristori die Hofkapelle vom Cembalo aus geleitet

Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurological disorders characterized primarily by a pyramidal syndrome with lower limb spasticity, which can manifest as pure HSP or associated with a number of neurological or non-neurological signs (i.e., complicated HSPs). The clinical variability of HSPs is associated with a wide genetic heterogeneity, with more than eighty causative genes known. Recently, next generation sequencing (NGS) has allowed increasing genetic definition in such a heterogeneous group of disorders. We report on a 56- year-old man affected by sporadic complicated HSP consisting of a pyramidal syndrome, cerebellar ataxia, congenital cataract, pes cavus, axonal sensory-motor peripheral neuropathy and cognitive decline. Brain MRI showed cerebellar atrophy and thin corpus callosum. By NGS we found a novel homozygous biallelic c.452-1G > C mutation in the b-glucosidase 2 gene (GBA2), known to be causative for autosomal recessive hereditary spastic paraplegia type 46 (SPG46). The rarity of this inherited form besides reporting on a novel mutation, expands the genetic and clinical spectrum of SPG46 related HSP

Steps towards collective sustainability in biomedical research

The optimism surrounding multistakeholder research initiatives does not match the clear view of policies that are needed to exploit the potential of these collaborations. Here we propose some action items that stem from the integration between research advancements with the perspectives of patient-advocacy organizations, academia, and industry

Genome-Wide Multiple Sclerosis Association Data and Coagulation

The emerging concept of a crosstalk between hemostasis, inflammation, and immune system prompt recent works on coagulation cascade in multiple sclerosis (MS). Studies on MS pathology identified several coagulation factors since the beginning of the disease pathophysiology: fibrin deposition with breakdown of blood brain barrier, and coagulation factors within active plaques may exert pathogenic role, especially through the innate immune system. Studies on circulating coagulation factors showed complex imbalance involving several components of hemostasis cascade (thrombin, factor X, factor XII). To analyze the role of the coagulation process in connection with other pathogenic pathways, we implemented a systematic matching of genome-wide association studies (GWAS) data with an informative and unbiased network of coagulation pathways. Using MetaCore (version 6.35 build 69300, 2018) we analyzed the connectivity (i.e., direct and indirect interactions among two networks) between the network of the coagulation process and the network resulting from feeding into MetaCore the MS GWAS data. The two networks presented a remarkable over-connectivity: 958 connections vs. 561 expected by chance; z-score = 17.39; p-value < 0.00001. Moreover, genes coding for cluster of differentiation 40 (CD40) and plasminogen activator, urokinase (PLAU) shared both networks, pointed to an integral interplay between coagulation cascade and main pathogenic immune effectors. In fact, CD40 pathways is especially operative in B cells, that are currently a major therapeutic target in MS field. The potential interaction of PLAU with a signal of paramount importance for B cell pathogenicity, such as CD40, suggest new lines of research and pave the way to implement new therapeutic targets

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan