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Marta Para-Prieto,1,2 Raul Martin,1,3,4 Sara Crespo,2 Laura Mena-Garcia,1 Andres Valisena,2 Lisandro Cordero,1 Gloria Gonzalez Fernandez,2 Juan F Arenillas,5 Nieves Tellez,5 Jose Carlos Pastor1,2 1Universidad de Valladolid, Instituto Universitario de Oftalmobiología Aplicada (IOBA Eye Institute), Valladolid, 47011, Spain; 2Hospital Clínico Universitario, Department of Ophthalmology, Valladolid, 47005, Spain; 3Universidad de Valladolid, Departamento de Física Teórica, Atómica y Óptica, Valladolid, 47011, Spain; 4Plymouth University, Faculty of Health and Human Sciences, Plymouth, UK; 5Hospital Clínico Universitario, Department of Neurology, Valladolid, 47005, SpainCorrespondence: Raul MartinIOBA Eye Institute, University of Valladolid, Paseo de Belen, 17, Valladolid, 47011, SpainTel +34 983 184 848Fax +34 983 184 762Email raul@ioba.med.uva.esObjective: To evaluate the agreement between the peripapillary retinal nerve fiber layer (pRNFL) and foveal thickness (FT) measurements among three different spectral domain-optical coherence tomography (SD-OCT) instruments in a sample of multiple sclerosis (MS) patients and a healthy age-matched control group.Methods: An observational cross-sectional study with three groups: healthy subjects and MS patients w/w a previous clinical diagnosis of optic neuritis (ON) was conducted. The pRNFL and FT were measured using three different SD-OCT instruments (OCT PRIMUS 200 and OCT CIRRUS 500 SD-OCT [Carl Zeiss Meditec] and OCT 3D 2000 [Topcon]).Results: Twenty eyes from 10 healthy subjects matched in age with MS patients without a previous history of eye disease and 62 MS eyes from 31 MS patients (29 eyes without history of ON and 33 eyes with history of ON) were enrolled. Healthy subjects and MS patients without ON did not show differences between the pRNFL and FT thickness (P> 0.99) with any of the instruments. However, MS eyes with a previous episode of ON showed thinner pRNFL and FT (P< 0.01). PRIMUS and CIRRUS OCT showed better agreement of the pRNLF and FT in both healthy and MS eyes. However, 3D OCT showed less agreement in the pRNFL measurement with CIRRUS in both healthy and MS eyes.Interpretation: Although OCT is a valuable technology to improve MS patient assessment, differences between devices must be taken into account. It is necessary to create an international group that standardizes the measurement conditions and above all that provides reference bases for normal subjects.Keywords: spectral-domain optical coherence tomography; SD-OCT, multiple sclerosis; MS, retinal nerve fiber layer; RNFL, foveal thickness; FT, variability

Byline: J. Rio (1), M. Tintore (1), C. Nos (1), N. Tellez (1), I. Galan (1), X. Montalban (1) Keywords: multiple sclerosis; interferon beta; observational study Abstract: Background and objective Long--term observational studies may provide additional information about the behaviour of different drugs in the post--marketing period. We present the data of our cohort of relapsing--remitting multiple sclerosis (RRMS) patients treated with interferon beta (IFN[beta]). Methods We analysed RRMS patients followed for at least 2 years. From 1995, we initiated therapy with IFN[beta].As they became available, patients were allocated to one of the IFNs at standard doses (IFN[beta]--1b, IFN[beta]--1a i. m. or IFN[beta]--1a s. c.). Each patient was included in a follow--up protocol containing demographic and baseline clinical data. Results Between 1995 and 2004, 382 patients have completed at least 2 years of follow--up. Significant differences at entry were observed. Patients on IFN[beta]--1b had a higher disease activity and disability at baseline than those on IFN[beta]--1a i. m. or IFN[beta]--1a s. c. A significant reduction in the relapse rate was observed for the three drugs (70 % for IFN[beta]--1b, 64% for IFN[beta]--1a i. m. and 74 % for IFN[beta]--1a s. c.). We observed a sustained progression of disability in 11% of patients on IFN[beta]--1b, 17% on IFN[beta]--1a i. m. and 19% on IFN[beta]--1a s. c. and at four years of follow--up in 24% of patients on IFN[beta]--1b, 23% on IFN[beta]--1a i. m. and 35% on IFN[beta]--1a s. c. No unexpected major adverse events were observed with any of the drugs. Conclusions Interferon beta is safe and well tolerated. The various registered interferon beta drugs provide a comparable efficacy in a large non--selected cohort of RRMS patients. Author Affiliation: (1) 2a planta, EUI Unitat de Neuroimmunologia Clinica, Hospital Universitario Vall d'Hebron, Psg.Vall d'Hebron 119-120, 08035, Barcelona, Spain Article History: Registration Date: 01/01/2005 Received Date: 28/04/2004 Accepted Date: 08/11/2004 Online Date: 18/03/2005

Objective Our objective in this study is to evaluate whether brain magnetic resonance imaging (MRI) performed at interferon-beta (IFN-β) onset and after 12 months allow us to identify relapsing-remitting multiple sclerosis (RRMS) patients with a disability increase in the first 2 years of therapy. Methods This is a prospective and longitudinal study of patients with RRMS treated with IFN-β. All patients included underwent brain MRI before the onset of therapy with IFN-β and 12 months after. MRI measures (T2, unenhanced T1-weighted and gadolinium-enhancing T1-weighted brain lesion load, brain parenchymal fraction) were undertaken at baseline and after 12 months. The number of active lesions (new or enlarging T2 plus gadolinium-enhancing brain lesions) was also assessed on the 12 months MRI scan. Expanded Disability Status Scale (EDSS) was scored every 3 months. We defined an increase in disability as an increase of at least 1 EDSS point confirmed and sustained during the first 2 years of therapy with IFN-β. Regression analysis was performed in order to identify MRI variables of response. Results We included 152 patients who were followed-up for at least 2 years. After 2 years of therapy, 24 patients (16%) had an increase in disability. The logistic regression model showed that active lesions in the scan performed at 12 months were the most important factor related with the increase of disability after 2 years of therapy (odds ratio 8.3, 95% confidence interval 3.1-21.9; p < 0.0001). Conclusions In RRMS patients treated with IFN-β the MRI changes occurring during the first year may have a prognostic value for identifying patients with a confirmed increase of disability after 2 years of therapy. [ABSTRACT FROM AUTHOR]

Cannabis has been consumed for centuries, but global regulatory changes over the past three decades have increased the availability and consumption of cannabis. Cannabinoids are touted to have therapeutic potential for many diseases and could be a replacement for opioids for analgesia and sedation. However, cannabinoids can cause substantial adverse cardiovascular events that would mitigate any potential benefit. The endocannabinoid system regulates mood, satiety and memory, and modulates the cardiovascular system. The link between cannabinoids and cardiovascular disease, which used to be limited to evidence from preclinical studies, case reports and case series, is now evident in epidemiological studies. Cannabinoids adversely affect the cardiovascular system, causing myocardial infarction, cerebrovascular accidents, arrhythmia and heart failure. The effects of novel cannabinoids are unknown, and synthetic cannabinoids have the potential to cause even more substantial harm than traditional cannabinoids. Therefore, with the increasing availability and use of cannabis, the acute and chronic effects of this drug are becoming apparent., Competing Interests: Competing interests: M.C. is a consultant for Greenstone Biosciences. J.C.W. is a co-founder and on the Scientific Advisory Board of Greenstone Biosciences. N.J.-T. declares no competing interests., (© 2025. Springer Nature Limited.)

Outer membrane vesicles (OMVs) are spherical structures that contain a small fraction of the periplasm of Gram-negative bacteria, surrounded by its outer membrane. They are naturally produced and detached from the bacterial surface, participate in diverse biological processes, and their diameter size is in the range of 10-300 nm. OMVs have gained interest in different applications, such as the development of biosensors, vaccines, protein chips, and the encapsulation of heterologous proteins and peptides expressed by these microorganisms. However, the use of OMVs in these applications is limited due to the low yields and high purification costs. In this study, we produced green fluorescent protein (GFP) encapsulated into OMVs using Escherichia coli JC8031 transformed with pTRC99A-ssTorA-GFP to establish the production and purification route. Results showed that the motility of the strain prevents its immobilization in alginate, which hampers the purification of OMVs. To address this issue, a zeolite-based column was used to chromatographically separate the OMVs from smaller particles. Further experiments will be focused on standardizing the production and purification of OMVs at a scalable level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Torres-Vanegas, Rincon-Tellez, Guzmán-Sastoque, Valderrama-Rincon, Cruz and Reyes.)

Cigarette smoking is positively and robustly associated with cardiovascular disease (CVD), including hypertension, atherosclerosis, cardiac arrhythmias, stroke, thromboembolism, myocardial infarctions, and heart failure. However, after more than a decade of ENDS presence in the U.S. marketplace, uncertainty persists regarding the long-term health consequences of ENDS use for CVD. New approach methods (NAMs) in the field of toxicology are being developed to enhance rapid prediction of human health hazards. Recent technical advances can now consider impact of biological factors such as sex and race/ethnicity, permitting application of NAMs findings to health equity and environmental justice issues. This has been the case for hazard assessments of drugs and environmental chemicals in areas such as cardiovascular, respiratory, and developmental toxicity. Despite these advances, a shortage of widely accepted methodologies to predict the impact of ENDS use on human health slows the application of regulatory oversight and the protection of public health. Minimizing the time between the emergence of risk (e.g., ENDS use) and the administration of well-founded regulatory policy requires thoughtful consideration of the currently available sources of data, their applicability to the prediction of health outcomes, and whether these available data streams are enough to support an actionable decision. This challenge forms the basis of this white paper on how best to reveal potential toxicities of ENDS use in the human cardiovascular system-a primary target of conventional tobacco smoking. We identify current approaches used to evaluate the impacts of tobacco on cardiovascular health, in particular emerging techniques that replace, reduce, and refine slower and more costly animal models with NAMs platforms that can be applied to tobacco regulatory science. The limitations of these emerging platforms are addressed, and systems biology approaches to close the knowledge gap between traditional models and NAMs are proposed. It is hoped that these suggestions and their adoption within the greater scientific community will result in fresh data streams that will support and enhance the scientific evaluation and subsequent decision-making of tobacco regulatory agencies worldwide., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Multiple sclerosis (MS) is a dysimmune and neurodegenerative disease of the central nervous system that continues to be one of the main causes of non-traumatic disability in young people despite the recent availability of highly effective drugs. Exercise-based interventions seem to have a positive impact on the course of the disease although pathophysiological mechanisms responsible for this benefit remain unclear. This is a longitudinal study to examine the effects of a short-term training program on neurofilament plasma levels, a biomarker of axonal destruction, measured using the ultrasensitive single molecule array (SiMoA). Eleven patients completed a 6-week supervised resistance-training program of 18 sessions that consisted of 3 sets of 8-10 repetitions of 7 exercises. Median plasma neurofilament levels significantly decreased from baseline (6.61 pg/ml) to 1 week after training intervention (4.44 pg/ml), and this effect was maintained after 4 weeks of detraining (4.38 pg/ml). These results suggest a neuroprotective effect of resistance training in this population and encourage us to investigate further the beneficial impact of physical exercise and to emphasize the importance of lifestyle in MS., (© 2023. Fondazione Società Italiana di Neurologia.)

Purpose: This retrospective cross-sectional, observational study aims to determine the correlation between demographic variables and nonsyndromic craniosynostosis., Methods: A cross-sectional study was carried out. The inclusion criteria were nonsyndromic craniosynostosis and the exclusion criteria were patients who did not have complete records., Results: The sample included 49 patients and mainly women. Patients with more than 4 days in the intensive care unit were related with more complications. Intracranial Hypertension was seen predominantly in patients between 6 and 8 months P =0007., Conclusion: Some variables can modificate complications risk but future studies are needed to further investigate the influence of such variables on craniofacial care., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by Mutaz B. Habal, MD.)

Exposure to commonly used anesthetics leads to neurotoxic effects in animal models-ranging from cell death to learning and memory deficits. These neurotoxic effects invoke a variety of molecular pathways, exerting either immediate or long-term effects at the cellular and behavioural levels. However, little is known about the gene expression changes following early neonatal exposure to these anesthetic agents. We report here on the effects of sevoflurane, a commonly used inhalational anesthetic, on learning and memory and identify a key set of genes that may likely be involved in the observed behavioural deficits. Specifically, we demonstrate that sevoflurane exposure in postnatal day 7 (P7) rat pups results in subtle, but distinct, memory deficits in the adult animals that have not been reported previously. Interestingly, when given intraperitoneally, pre-treatment with dexmedetomidine (DEX) could only prevent sevoflurane-induced anxiety in open field testing. To identify genes that may have been altered in the neonatal rats after sevoflurane and DEX exposure, specifically those impacting cellular viability, learning, and memory, we conducted an extensive Nanostring study examining over 770 genes. We found differential changes in the gene expression levels after exposure to both agents. A number of the perturbed genes found in this study have previously been implicated in synaptic transmission, plasticity, neurogenesis, apoptosis, myelination, and learning and memory. Our data thus demonstrate that subtle, albeit long-term, changes observed in an adult animal's learning and memory after neonatal anesthetic exposure may likely involve perturbation of specific gene expression patterns.

Long QT syndrome (LQTS) is an inherited cardiovascular disorder characterized by electrical conduction abnormalities leading to arrhythmia, fainting, seizures, and an increased risk of sudden death. There are over 15 genes involved in causing LQTS, including SNTA1. Here we generated two human-induced pluripotent stem cell (iPSC) lines from two LQT patients carrying a missense mutation in SNTA1 (c.1088A > C). Both lines showed normal morphological properties, expressed pluripotency markers, showed a normal karyotype profile, and had the ability to differentiate into the three germ layers, making them a valuable tool to model LQTS to investigate the pathological mechanisms related to this SNTA1 variant., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Anesthetics have been shown to cause cytotoxicity, cell death, affect neuronal growth and connectivity in animal models; however, their effects on learning and memory remain to be fully defined. Here, we examined the effects of the inhalation anesthetic sevoflurane (SEV)-both in vivo by examining learning and memory in freely behaving animals, and in vitro using cultured neurons to assess its impact on viability, mitochondrial structure, and function. We demonstrate here that neonatal exposure to sub-clinically used concentrations of SEV results in significant, albeit subtle and previously unreported, learning and memory deficits in adult animals. These deficits involve neuronal cell death, as observed in cell culture, and are likely mediated through perturbed mitochondrial structure and function. Parenthetically, both behavioural deficits and cell death were prevented when the animals and cultured neurons were pre-treated with the anesthetic adjuvant Dexmedetomidine (DEX). Taken together, our data provide direct evidence for sevoflurane-induced cytotoxic effects at the neuronal level while perturbing learning and memory at the behavioural level. In addition, our data underscore the importance of adjuvant agents such as DEX that could potentially counter the harmful effects of commonly used anesthetic agents for better clinical outcomes.

Recent animal studies have drawn concerns regarding most commonly used anesthetics and their long-term cytotoxic effects, specifically on the nervous tissue. It is therefore imperative that the search continues for agents that are non-toxic at both the cellular and behavioural level. One such agent appears to be dexmedetomidine (DEX) which has not only been found to be less neurotoxic but has also been shown to protect neurons from cytotoxicity induced by other anesthetic agents. However, DEX's effects on the growth and synaptic connectivity at the individual neuronal level, and the underlying mechanisms have not yet been fully resolved. Here, we tested DEX for its impact on neuronal growth, synapse formation (in vitro) and learning and memory in a rodent model. Rat cortical neurons were exposed to a range of clinically relevant DEX concentrations (0.05-10 µM) and cellular viability, neurite outgrowth, synaptic assembly and mitochondrial morphology were assessed. We discovered that DEX did not affect neuronal viability when used below 10 µM, whereas significant cell death was noted at higher concentrations. Interestingly, in the presence of DEX, neurons exhibited more neurite branching, albeit with no differences in corresponding synaptic puncta formation. When rat pups were injected subcutaneously with DEX 25 µg/kg on postnatal day 7 and again on postnatal day 8, we discovered that this agent did not affect hippocampal-dependent memory in freely behaving animals. Our data demonstrates, for the first time, the non-neurotoxic nature of DEX both in vitro and in vivo in an animal model providing support for its utility as a safer anesthetic agent. Moreover, this study provides the first direct evidence that although DEX is growth permissive, causes mitochondrial fusion and reduces oxygen reactive species production, it does not affect the total number of synaptic connections between the cortical neurons in vitro., (© 2021. The Author(s).)

Anesthetics are deemed necessary for all major surgical procedures. However, they have also been found to exert neurotoxic effects when tested on various experimental models, but the underlying mechanisms remain unknown. Earlier studies have implicated mitochondrial fragmentation as a potential target of anesthetic-induced toxicity, although clinical strategies to protect their structure and function remain sparse. Here, we sought to determine if preserving mitochondrial networks with a non-toxic, short-life synthetic peptide-P110, would protect cortical neurons against both inhalational and intravenous anesthetic-induced neurotoxicity. This study provides the first direct and comparative account of three key anesthetics (desflurane, propofol, and ketamine) when used under identical conditions, and demonstrates their impact on neonatal, rat cortical neuronal viability, neurite outgrowth and synaptic assembly. Furthermore, we discovered that inhibiting Fis1-mediated mitochondrial fission reverses anesthetic-induced aberrations in an agent-specific manner. This study underscores the importance of designing mitigation strategies invoking mitochondria-mediated protection from anesthetic-induced toxicity in both animals and humans.

We used patient dermal fibroblasts to characterize the mitochondrial abnormalities associated with the dilated cardiomyopathy with ataxia syndrome (DCMA) and to study the effect of the mitochondrially-targeted peptide SS-31 as a potential novel therapeutic. DCMA is a rare and understudied autosomal recessive disorder thought to be related to Barth syndrome but caused by mutations in DNAJC19 , a protein of unknown function localized to the mitochondria. The clinical disease is characterized by 3-methylglutaconic aciduria, dilated cardiomyopathy, abnormal neurological development, and other heterogeneous features. Until recently no effective therapies had been identified and affected patients frequently died in early childhood from intractable heart failure. Skin fibroblasts from four pediatric patients with DCMA were used to establish parameters of mitochondrial dysfunction. Mitochondrial structure, reactive oxygen species (ROS) production, cardiolipin composition, and gene expression were evaluated. Immunocytochemistry with semi-automated quantification of mitochondrial structural metrics and transmission electron microscopy demonstrated mitochondria to be highly fragmented in DCMA fibroblasts compared to healthy control cells. Live-cell imaging demonstrated significantly increased ROS production in patient cells. These abnormalities were reversed by treating DCMA fibroblasts with SS-31, a synthetic peptide that localizes to the inner mitochondrial membrane. Levels of cardiolipin were not significantly different between control and DCMA cells and were unaffected by SS-31 treatment. Our results demonstrate the abnormal mitochondria in fibroblasts from patients with DCMA and suggest that SS-31 may represent a potential therapy for this devastating disease., (Copyright © 2019 Machiraju, Wang, Sabouny, Huang, Zhao, Iqbal, King, Prasher, Lodha, Jimenez-Tellez, Ravandi, Argiropoulos, Sinasac, Khan, Shutt and Greenway.)

The genetic cardiomyopathies are a group of disorders related by abnormal myocardial structure and function. Although individually rare, these diseases collectively represent a significant health burden since they usually develop early in life and are a major cause of morbidity and mortality amongst affected children. The heterogeneity and rarity of these disorders requires the use of an appropriate model system in order to characterize the mechanism of disease and develop useful therapeutics since standard drug trials are infeasible. A common approach to study human disease involves the use of animal models, especially rodents, but due to important biological and physiological differences, this model system may not recapitulate human disease. An alternative approach for studying the metabolic cardiomyopathies relies on the use of cellular models which have most frequently been immortalized cell lines or patient-derived fibroblasts. However, the recent introduction of induced pluripotent stem cells (iPSCs), which have the ability to differentiate into any cell type in the body, is of great interest and has the potential to revolutionize the study of rare diseases. In this paper we review the advantages and disadvantages of each model system by comparing their utility for the study of mitochondrial cardiomyopathy with a particular focus on the use of iPSCs in cardiovascular biology for the modeling of rare genetic or metabolic diseases., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials., Competing Interests: Conflict of interest statement: E.F. and L.S. published an obituary on two leaders in MS [Kildebeck EJ, et al. (2017) The emergence of neuroepidemiology, neurovirology and neuroimmunology: The legacies of John F. Kurtzke and Richard “Dick” T. Johnson. J Neurol 264:817–828]. I.Z. has received travel reimbursement from Genzyme, Biogen, and Merck for national and international meetings over the last 3 y. E.H.M.-L. has received speaker honoraria from Biogen, Roche, Novartis, and Sanofi and a travel reimbursement from Biogen, Roche, Novartis, and Sanofi. E.H.M.-L. has participated in advisory boards for Roche and Sanofi. A.S. has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd., Roche, and Novartis. S.L. has received speaker honoraria and travel reimbursement from Biogen, Merck, Novartis, and Teva. I.P.-V. has received travel reimbursement from Roche Spain and Genzyme-Sanofi, European Academy of Neurology, and the European Committee for Treatment and Research in Multiple Sclerosis for international and national meetings over the last 3 y; I.P.-V. holds a patent for an affordable eye-tracking system to measure eye movement in neurologic diseases and holds stock in Aura Innovative Robotics. N.S.-V. received compensation for consulting services and speaker honoraria from Genzyme-Sanofi, Biogen idec, Merck-Serono, and Bayer-Schering. P.V. holds stocks and has received compensation from Bionure Farma SL; Health Engineering SL; Spiral Therapeutics, Inc.; and QMenta SL. L.S. received compensation from Novartis, Celgene, Bionure, Tolerion, Katexco, Atreca, and TG Therapeutics. All other authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: Chronic periodontitis is a multifactorial infectious disease, where multiple bacteria, such as Porphyromonas gingivalis , Prevotella intermedia , and Fusobacterium nucleatum are implicated. The main purpose of researching natural products is to find substances or compounds with antimicrobial activity., Aim: The objective of this work was to determine antimicrobial activity from extracts and obtained fractions from Piper marginatum Jacq and Ilex guayusa Loes on P. gingivalis ATCC 33277, F. nucleatum ATCC 25586, and P. intermedia ATCC 25611., Methods: Total ethanol extracts were obtained from both plants. Fractions were obtained from total ethanol extracts with amberlite as a stationary phase employing hexane, acetone, and ethanol-water as solvents. Qualitative and quantitative phytochemical characterization was performed on total ethanol extracts from both plants. Antimicrobial activity from total ethanol extracts and fractions from both plants were evaluated on P. gingivalis ATCC 33277, F. nucleatum ATCC 25586, and P. intermedia ATCC by the well diffusion method with Wilkins-Chalgren agar., Results: Piper marginatum Jacq total ethanol extract presented antimicrobial activity against all three bacteria, whereas Ilex guayusa Loes was only efficient against P. gingivalis ATCC 33277 and P. intermedia ATCC 25611, with inhibition halos from 9.3 to 30 mm. Ilex guayusa Loes obtained fractions presented antimicrobial activity against all three microorganisms evaluated, with inhibition halos ranging from 9.7 to 18.7 mm. In regards to Piper marginatum Jacq fractions, inhibition halos were between 8.3 and 19 mm, against all three microorganisms evaluated; only hexane fraction did not present antimicrobial activity against F. nucleatum ATCC 25586., Conclusion: Piper marginatum Jacq and Ilex guayusa Loes total ethanol extracts and fractions presented outstanding antimicrobial activity against P. gingivalis ATCC 33277, P. intermedia ATCC 25611, and F. nucleatum ATCC 25586.

The Post-ECTRIMS Meeting is an emblematic event in the field of multiple sclerosis in Spain. Its chief aim is bring together the country's leading specialist neurologists to analyse the main advances made in multiple sclerosis and to review the most important topics addressed at the ECTRIMS Congress. The tenth Post-ECTRIMS Meeting was held in November 2017. Over the years this event has firmly established itself as an important meeting point where experts from all over the country get together to foster communication, establish synergies and promote and enhance research ultimately aimed at improving the prognosis and quality of life of patients with multiple sclerosis. This second part addresses the different strategies for the management of patients in advanced stages of the disease and the safety of therapy in multiple sclerosis. Likewise, attention is also drawn to the areas that require further scientific and clinical evidence. In this edition, particular importance is given to multiple sclerosis in the paediatric population and ageing in the disease. At the same time emphasis is placed on the need to conduct collaborative studies and to foster greater awareness among specialists regarding the detection and management of the comorbidities in multiple sclerosis.

Introduction: Ocrelizumab is a humanised monoclonal antibody that targets the CD20 antigen on B cells. It has recently been approved by the US (Food and Drug Administration) and European health agencies (European Medicines Agency) for the treatment of multiple sclerosis (MS) and is the first drug marketed for both relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). The clinical trials conducted for both the relapsing forms (OPERA I/II) and the progressive forms of the disease (ORATORIO) have demonstrated its efficacy. The aim of this review is to address the main aspects of the efficacy and safety of ocrelizumab in MS., Development: Using PubMed, a literature review was conducted of studies published at the ECTRIMS 2017 Congress and of active studies in ClinicalTrials. In order to evaluate the efficacy and safety of ocrelizumab in MS, both randomised clinical trials and their extension and follow-up studies were reviewed, and information about its safety obtained from monitoring programmes of the Food and Drug Administration and European Medicines Agency was included., Conclusions: Ocrelizumab is the first drug that has been shown to be able to significantly slow disability progression at 12 and 24 weeks in patients with PPMS. It is also effective in controlling clinical and radiological activity in patients with RRMS forms, and it is approved and indicated for both phenotypes of the disease. To date, the safety profile of ocrelizumab matches that observed in clinical trials, without any unexpected alerts.

Reprogramming acinar cells into insulin producing cells using adenoviral (Ad)-mediated delivery of Pdx1, Ngn3 and MafA (PNM) is an innovative approach for the treatment of diabetes. Here, we aimed to investigate the molecular mechanisms involved in this process and in particular, the role of microRNAs. To this end, we performed a comparative study of acinar-to-β cell reprogramming efficiency in the rat acinar cell line AR42J and its subclone B13 after transduction with Ad-PNM. B13 cells were more efficiently reprogrammed than AR42J cells, which was demonstrated by a strong activation of β cell markers (Ins1, Ins2, IAPP, NeuroD1 and Pax4). miRNome panels were used to analyze differentially expressed miRNAs in acinar cells under four experimental conditions (i) non-transduced AR42J cells, (ii) non-transduced B13 cells, (iii) B13 cells transduced with Ad-GFP vectors and (iv) B13 cells transduced with Ad-PNM vectors. A total of 59 miRNAs were found to be differentially expressed between non-transduced AR42J and B13 cells. Specifically, the miR-200 family was completely repressed in B13 cells, suggesting that these cells exist in a less differentiated state than AR42J cells and as a consequence they present a greater plasticity. Adenoviral transduction per se induced dedifferentiation of acinar cells and 11 miRNAs were putatively involved in this process, whereas 8 miRNAs were found to be associated with PNM expression. Of note, Ad-PNM reprogrammed B13 cells presented the same levels of miR-137-3p, miR-135a-5p, miR-204-5p and miR-210-3p of those detected in islets, highlighting their role in the process. In conclusion, this study led to the identification of miRNAs that might be of compelling importance to improve acinar-to-β cell conversion for the future treatment of diabetes.

The new insights presented at the 5th Joint Triennial Congress of the European and Americas Committees on Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS) held in Amsterdam, the Netherlands, 19-22 October 2011, have been summarized at the fourth edition of Post-ECTRIMS meeting held in Madrid in November 2011. Regional grey-matter atrophy is more sensitive to cognitive impairment than global grey-matter atrophy measures. In patients with clinically isolated syndrome cognitive impairment does not predict conversion to multiple sclerosis (MS) after 5-years of follow-up. Focusing on central nervous system plasticity and functional reorganization in MS, an early intervention can improve clinical aspects and enhances brain plasticity. Preservation of a potential for plasticity provides a rationale for rehabilitation interventions even in later stages of disease. Therapeutical strategies have focused on stem cell-mediated remyelination and immunomodulation functions, on cellular infiltration into the brain, and on new ways for immuno-modulation for the development of future therapies in MS. Encouraging findings from clinical trials with current and emerging disease-modifying therapy being developed was also a key theme at this edition. Positive results have been reported for rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab, teriflunomide, BG-12, and laquinimod, including a favorable safety profile. Since armamentarium for the treatment of MS is fast increasing, concerns exist about the risk of severe adverse events with their use. This aspect reinforces the importance of disease registries as a proactive tool for monitoring drug safety in the post-approval setting.

Introduction: Thirty per cent of patients with multiple sclerosis (MS) present a suboptimal response to treatment in the first few years. The real impact of the change of treatment has still not been well established., Aims: To describe our clinical practice with regard to the change of treatment in MS patients with a suboptimal response and to analyse their progress depending on our therapeutic decisions., Patients and Methods: The study is observation-based and retrospective. The sample was made up of patients with relapsing-remitting MS and at least one event after establishing immunomodulatory treatment. Both the intention to change treatment and the delays until the actual change took place were taken into account. The theoretical consequences of these strategies were measured by the changes in the expected curve of the Multiple Sclerosis Severity Scale (MSSS)., Results: A comparison of those who changed immunomodulator with those that did not showed that 64.3% versus 35.3%, respectively, improved on the expected curve of the MSSS (p > 0.05). Patients who improved the expected curve of the MSSS had changed treatment before those who did not improve (1.9 months versus 6 months), although the differences were not significant. The mean time that elapsed between taking the decision to change and actually changing the treatment was 2.70 ± 3.55 months., Conclusions: Despite limitations due to the size of the sample, the patients with a suboptimal response who changed treatment early could benefit from an improvement in their expected progression on the MSSS.

AIM. To study the frequency, safety and efficacy of perfusion computed tomography (PCT), through identification of brain tissue-at-risk, to guide intravenous thrombolysis in stroke patients with regulatory exclusion criteria (SITS-MOST and ECASS-3). PATIENTS AND METHODS. We studied consecutive acute non-lacunar ischemic stroke patients. After conventional CT was considered eligible, PCT was performed in the following circumstances: 4.5 to 6 h window, wake-up stroke or unknown time of onset; extent early infarct signs on CT; minor or severe stroke; seizures or loss of consciousness. Intravenous 0.9 mg/kg alteplase was indicated if: cerebral blood volume lesion covered < 1/3 of middle cerebral artery territory; mismatch > 20% between mean transit time and cerebral blood volume maps existed; and informed consent. SITS-MOST safety-efficacy parameters were used as endpoint variables. RESULTS. Between May 2009-April 2010, 66 hyperacute ischemic stroke patients a priori not eligible for intravenous thrombolysis underwent PCT. Indications were: > 4.5 h in 18 patients, wake up stroke or unknown onset in 25, extent infarct signs in 6, seizures at onset in 11, and minor stroke (NIHSS < 4) in 6. Twenty-nine (44%) of them finally received intravenous thrombolysis. Symptomatic hemorrhagic transformation occurred in 2 (6.9%) patient and 18 (62.1%) achieved a modified Rankin scale score equal or less than 2 on day 90. CONCLUSION. A high proportion of acute stroke patients with SITS-MOST and ECASS-3 exclusion criteria can be safely and efficaciously treated with intravenous thrombolysis using a PCT selection protocol. However randomized control trials will be needed to confirm our results.

Objective: Our objective in this study is to evaluate whether brain magnetic resonance imaging (MRI) performed at interferon-beta (IFN-beta) onset and after 12 months allow us to identify relapsing-remitting multiple sclerosis (RRMS) patients with a disability increase in the first 2 years of therapy., Methods: This is a prospective and longitudinal study of patients with RRMS treated with IFN-beta. All patients included underwent brain MRI before the onset of therapy with IFN-beta and 12 months after. MRI measures (T2, unenhanced T1-weighted and gadolinium-enhancing T1-weighted brain lesion load, brain parenchymal fraction) were undertaken at baseline and after 12 months. The number of active lesions (new or enlarging T2 plus gadolinium-enhancing brain lesions) was also assessed on the 12 months MRI scan. Expanded Disability Status Scale (EDSS) was scored every 3 months. We defined an increase in disability as an increase of at least 1 EDSS point confirmed and sustained during the first 2 years of therapy with IFN-beta. Regression analysis was performed in order to identify MRI variables of response., Results: We included 152 patients who were followed-up for at least 2 years. After 2 years of therapy, 24 patients (16%) had an increase in disability. The logistic regression model showed that active lesions in the scan performed at 12 months were the most important factor related with the increase of disability after 2 years of therapy (odds ratio 8.3, 95% confidence interval 3.1-21.9; p < 0.0001)., Conclusions: In RRMS patients treated with IFN-beta the MRI changes occurring during the first year may have a prognostic value for identifying patients with a confirmed increase of disability after 2 years of therapy.

Several foci of lobomycosis among Colombian Amer Indians population were described in the Casanare region of Colombia, near the Orinoco river on the Colombian-Venezuelan border. This paper reports 16 new patients. The prevalence of Lobo's disease was 8.5% in the Amoruas tribe. Nodular lesions were located on the elbow, scapular and lumbar regions, knees, feet and legs. Leg lesions were especially numerous, were confluent and tended to ulcerate. All cases were confirmed histologically. Two Negro patients were also described. The cases bring the total number of confirmed patients with lobomycosis in Colombia to 41. Twenty-five of these were Amer Indian patients from tribes living in the Orinoco and Amazon basins of the country.