Human endogenous retroviruses (HERVs) arise from ancient infections of the host germline cells by exogenous retroviruses, constituting 8% of the human genome. Elevated level of envelope transcripts from HERVs-W has been detected in CSF, plasma and brain tissues from patients with Multiple Sclerosis (MS), most of them from Xq22.3, 15q21.3, and 6q21 chromosomes. However, since the locus Xq22.3 (ERVWE2) lack the 5′ LTR promoter and the putative protein should be truncated due to a stop codon, we investigated the ERVWE2 genomic loci from 84 individuals, including MS patients with active HERV-W expression detected in PBMC. In addition, an automated search for promoter sequences in 20 kb nearby region of ERVWE2 reference sequence was performed. Several putative binding sites for cellular cofactors and enhancers were found, suggesting that transcription may occur via alternative promoters. However, ERVWE2 DNA sequencing of MS and healthy individuals revealed that all of them harbor a stop codon at site 39, undermining the expression of a full-length protein. Finally, since plaque formation in central nervous system (CNS) of MS patients is attributed to immunological mechanisms triggered by autoimmune attack against myelin, we also investigated the level of similarity between envelope protein and myelin oligodendrocyte glycoprotein (MOG). Comparison of the MOG to the envelope identified five retroviral regions similar to the Ig-like domain of MOG. Interestingly, one of them includes T and B cell epitopes, capable to induce T effector functions and circulating Abs in rats. In sum, although no DNA substitutions that would link ERVWE2 to the MS pathogeny was found, the similarity between the envelope protein to MOG extends the idea that ERVEW2 may be involved on the immunopathogenesis of MS, maybe facilitating the MOG recognizing by the immune system. Although awaiting experimental evidences, the data presented here may expand the scope of the endogenous retroviruses involvement on MS pathogenesis.

Background: Ketamine has been shown to produce a rapid and robust antidepressant effect. Though numerous routes of administration have been studied, subcutaneous (SC) has proven to be a convenient and cost-effective route making its use particularly relevant in developing countries. Here we provide a systematic review covering the use of SC racemic ketamine and esketamine in depression, including its efficacy, safety and tolerability.Methods: A systematic literature search was carried out, from inception through March, 2021, using PubMed/MEDLINE, EMBASE and Web of Science, with no limits of language. After identifying 159 potentially relevant articles, 12 articles were selected after applying our inclusion/exclusion criteria. These comprised two randomized clinical trials, five case-reports and five retrospective studies. Given the small number of studies found and their heterogeneous nature, a meta-analysis was not considered appropriate. Here we provide a synthesis of these data including participant characteristics, dose range, efficacy, safety/ tolerability. Risk of bias was accessed using the Cochrane risk of bias tool.Results: SC Ketamine was administered to unipolar and bipolar patients a single or multiple doses, weekly or twice-weekly, a dose-titration approach was made in major studies, dose ranged from 0.1 to 0.5 mg/Kg of racemic ketamine and 0.5–1 mg/Kg of esketamine. Across all studies, SC ketamine showed a rapid and robust antidepressant effect, with response/ remission rates from 50 to 100% following both single or multiple doses, with transitory side effects.Conclusion: SC racemic ketamine and esketamine in depression is a promising strategy showing beneficial efficacy and tolerability. Future studies exploring the SC route, its cost-effectiveness, and a direct comparison with IV and intranasal (IN) protocols are warranted.Systematic Review Registration: CRD42019137434

CONTEXT AND OBJECTIVE: Patients undergoing the same neuromodulation protocol may present different responses. Computational models may help in understanding such differences.

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Multiple sclerosis is the most common autoimmune inflammatory demyelinating disease of the central nervous system, and its etiology is believed to have both genetic and environmental components. Several viruses have already been implicated as triggers and there are several studies that implicate members of the Herpesviridae family in the pathogenesis of MS. The most important characteristic of these viruses is that they have periods of latency and exacerbations within their biological sanctuary, the central nervous system. The Epstein-Barr, cytomegalovirus, human herpesvirus 6 and human herpesvirus 7 viruses are the members that are most studied as being possible triggers of multiple sclerosis. According to evidence in the literature, the herpesvirus family is strongly involved in the pathogenesis of this disease, but it is unlikely that they are the only component responsible for its development. There are probably multiple triggers and more studies are necessary to investigate and define these interactions.

Introduction: First-line treatment for obsessive-compulsive disorder (OCD) includes exposure and response prevention behavioral therapy and serotonin reuptake inhibitors, particularly in combination. New and more effective treatments are needed, give that recent studies suggest that glutamatergic neurotransmission contributes to the pathophysiology of the disorder. In these circumstances, ketamine, as a potent N-methyl-D-aspartate receptor antagonist and glutamate modulator, offers alternative possibilities for OCD treatment. Methods: This systematic review aims to investigate the effects of ketamine in OCD, following the Preferred Reporting Items for Systematic Review and Meta-analyses Protocols (PRISMA-P). Searches were carried out using the PubMed/ MEDLINE, Embase, and PsycINFO databases. Results: Nine articles were included, of which three were randomized controlled trials, three case reports, two open-label trials, and one a retrospective chart review. Reported data have shown a potential for fast onset of action and good tolerability of ketamine for OCD, even though the principal studies used only single-session racemic ketamine treatments, administered intravenously, and the results have been erratic. In addition, none of the available evidence demonstrates whether racemic ketamine, S-ketamine, or R-ketamine has the best efficacy in controlling OCD symptoms, and only sparse evidence suggests that a combination of ketamine and psychotherapy could benefit patients with OCD. Conclusion:In order to advance clinical practice regarding the use of ketamine in treating OCD, future randomized, double-blind, placebo-controlled trials are required. These trials need to use larger samples to explore ketamine and its enantiomers, with different methods of administration, multiple sessions, and appropriate washout periods.

This article describes the clinical and radiological evolution of a stable group of patients with relapsing-remitting multiple sclerosis that had their disease-modifying therapy (DMT) withdrawn. Forty patients, which had made continuous use of one immunomodulator and had remained free of disease for at least 5 years, had their DMT withdrawn and were observed from 13 to 86 months. Out of the followed patients, 4 (10%) patients presented with new attacks. In addition to these patients, 2 (5%) patients had new lesions revealed by magnetic resonance imaging that did not correspond to clinical attacks. Despite these results, the difficult decision to withdraw medication requires careful analysis. Withdrawal, however, should not be viewed as simply the suspension of treatment because these patients should be evaluated periodically, and the immunomodulators should be readily reintroduced if new attacks occur. Nonetheless, medication withdrawal is an option for a select group of patients.

CONTEXT AND OBJECTIVE: Multiple sclerosis (MS) is a chronic, immune-mediated and degenerative central nervous system (CNS) disease with well-established diagnostic criteria. Treatment can modify the course of the disease. The objective of this study was to describe the initial symptoms of multiple sclerosis in a Brazilian medical center. DESIGN AND SETTING: Descriptive study, conducted in a Brazilian reference center for multiple sclerosis treatment. METHODS: Data on 299 patients with confirmed diagnoses of MS were included in the study. Their medical files were evaluated and the data were analyzed. RESULTS:The most common symptom involved the cranial nerves (50.83%) and unifocal manifestation was presented by the majority of this population (73.91%). The mean time between the first symptom and the diagnosis was 2.84 years. Unifocal symptoms correlated with longer time taken to establish the diagnosis, with an average of 3.20 years, while for multifocal symptoms the average time taken for the diagnosis was 1.85 years. Unifocal onset was related to greater diagnostic difficulty. CONCLUSIONS: MS is a heterogeneous disease and its initial clinical manifestation is very variable. RESUMO CONTEXTO E OBJETIVO:A esclerose múltipla (EM) é uma doença crônica do sistema nervoso central (SNC) imunomediada e degenerativa, com critérios diagnósticos bem estabelecidos. O tratamento pode modificar o curso da doença. O objetivo deste estudo foi descrever os sintomas iniciais da esclerose múl-tipla em um centro médico brasileiro. TIPO DE ESTUDO E LOCAL: Estudo descritivo, conduzido em um centro médico de referência no tratamento de EM no Brasil. MÉTODOS: Foram incluídos no estudo dados de 299 pacientes com diagnóstico confirmado de EM. Seus prontuários foram avaliados e os dados foram analisados. RESULTADOS: O sintoma mais comum encontrado envolveu nervos cranianos (50,83%) e a manifestação unifocal foi apresentada pela maioria da população estudada (73,91%). O tempo médio entre o primeiro sintoma e o diagnóstico foi de 2,84 anos. O sintoma unifocal foi relacionado com maior tempo para o estabelecimento do diagnóstico, com uma média de 3,20 anos; enquanto para os sintomas multifocais, a mé-dia foi de 1,85 anos para o diagnóstico. O início unifocal foi relacionado a maior dificuldade de diagnóstico. CONCLUSÕES: EM é uma doença heterogênea e sua manifestação clínica inicial é muito variável.