Dimethyl fumarate in the management of multiple sclerosis: Appropriate patient selection and special considerations

Delayed-release dimethyl fumarate (DMF), also known as gastroresistant DMF, is the most recently approved oral disease-modifying treatment (DMT) for relapsing multiple sclerosis. Two randomized clinical trials (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing–Remitting MS [DEFINE] and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis [CONFIRM]) demonstrated significant efficacy in reducing relapse rate and radiological signs of disease activity, as seen on magnetic resonance imaging. The DEFINE study also indicated a significant effect of DMF on disability worsening, while the low incidence of confirmed disability worsening in the CONFIRM trial rendered an insignificant reduction among the DMF-treated groups when compared to placebo. DMF also demonstrated a good safety profile and acceptable tolerability, since the most common side effects (gastrointestinal events and flushing reactions) are usually transient and mild to moderate in severity. Here, we discuss the place in therapy of DMF for individuals with relapsing multiple sclerosis, providing a tentative therapeutic algorithm to manage newly diagnosed patients and those who do not adequately respond to self-injectable DMTs. Literature data supporting the potential role of DMF as a first-line therapy are presented. The possibility of using DMF as switching treatment or even as an add-on strategy in patients with breakthrough disease despite self-injectable DMTs will also be discussed. Lastly, we argue about the role of DMF as an exit strategy from natalizumab-treated patients who are considered at risk for developing multifocal progressive leukoencephalopathy

Dentate nucleus connectivity in adult patients with multiple sclerosis: functional changes at rest and correlation with clinical features

Background and objective: The dentate nucleus, which is the largest of the cerebellar nuclei, plays a critical role in movement and cognition. The aim of our study was to assess any changes in dentate functional connectivity (FC) in adult relapsing remitting multiple sclerosis (RR-MS) patients and to investigate possible clinical correlates. Materials and methods: In all, 54 patients and 24 healthy subjects (HS) underwent multimodal magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), three-dimensional-T1-weighted and resting state (RS) functional images; they also underwent a cognitive evaluation, that is, attention and information processing speed, by means of the Paced Auditory Serial Addition Test (PASAT). Patients were also scored according to Expanded Disability Status Scale (EDSS). RS-MRI data were analysed using FMRIB Software Library (FSL) tools, with the seed-based method to identify dentate FC. Results: When compared with HS, patients exhibited brain atrophy and widespread DTI abnormalities, as well as greater FC between the dentate nucleus and cortical areas, particularly in the frontal and parietal lobes. Within these areas, FC in patients correlated inversely with clinical impairment. Finally, FC correlated inversely with lesion load and microstructural brain damage. Conclusion: Our findings indicate that dentate FC at rest is altered in MS patients. Whether these functional changes are induced by the disease and play a compensatory role remains to be established

Functional connectivity changes and their relationship with clinical disability and white matter integrity in patients with relapsing-remitting multiple sclerosis

Background and objective: To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural brain damage, as assessed by diffusion tensor maging, and clinical impairments. Methods: Thirty relapsing–remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with GeneralLinear-Model and corrected for multiple comparisons. Results: Patients showed decreased functional connectivity in 5 of 11 resting-state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity. Conclusions: Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities

In vitro evaluation of toxic effects, bioavailability and bioaccesibility of beauvericin, enniatins and fusaproliferin = Evaluación in vitro de los efectos tóxicos, biodisponibilidad y bioacesibilidad de beuavericina, eniantinas y fusaproliferina

Los hongos de Fusarium pueden producir micotoxinas hexadepsipeptidicas, como beauvericina (BEA) y eniatinas (ENs) e isoprenoides como la fusaproliferina (FUS), las cuales se encuentran de forma natural en los alimentos y piensos. En las últimas décadas se han publicado datos, aunque escasos, sobre su toxicidad potencial en humanos y animales. Los objectivos de esta tesis fueron evaluar: los efectos citotóxicos de las FUS, BEA y ENs A, A1, B y B1 en células Caco-2, CHO-K1 y HT-29; los efectos citotóxicos de las ENs combinadas, la generación de especies reactivas de oxígeno (ROS) y la producción de peroxidación lipídica (LPO) tras exposición a FUS, BEA y ENs en las células Caco-2; la citoprotección del glutatión (GSH) y de polifenoles frente a la citotoxicidad de las ENs y BEA en las células Caco-2 y CHO-K1. Además, se determinó el efecto de la BEA y ENs sobre el ciclo celular, apoptosis/necrosis, la alteración de la membrana mitocondrial y efectos genotoxicos tras su exposición en células Caco-2; la biodisponibilidad de BEA y FUS mediante las células Caco-2 y la bioaccesibilidad de ENs A, A1, B y B1 a partir de cereales contaminados artificialmente. Los resultados demostraron que BEA y las ENs A, A1, B y B1 son citotóxicas dependiendo de la dosis y tiempo en las células Caco-2, HT-29 y CHO-K1. Las células CHO-K1 y Caco-2 fueron más sensibles a las ENs del grupo B y del grupo A, respectivamente. FUS no mostró efectos citotóxicos en el rango de concentraciones ensayadas. Se observó efecto sinérgico con las combinaciones de las ENs A1+B, A1+B1 y A+A1+B1 en las células Caco-2; mientras que la combinación de ENs B+B1 a bajas concentraciones mostraron efecto sinérgico. Se produjo estrés oxidativo en las células Caco-2 tras exponerlas a BEA y ENs en el siguiente orden: EN A1=EN A>EN B1>BEA>EN B. Como consecuencia del daño oxidativo se produjo LPO en el orden: BEA>EN A>EN A1=EN B1>EN B. FUS no produjo daño oxidativo. BEA redujo los niveles de GSH y aumentó los de glutatión oxidado (GSSG) en células Caco-2; mientras que los polifenoles mostraron efecto citoprotector en las células CHO-K1 (t-pterostilbeno>miricetina>rutina>quercetina 3-β-glucosido>quercetina) frente a la citotoxicidad inducida por las ENs. La BEA y ENs detuvieron el ciclo celular en la fase G2/M, lo cual se relaciona con el desequilibrio oxidativo inducido por la BEA y el daño al ADN inducido por las ENs A y A1 en las células Caco-2. Además, se observó muerte celular por apoptosis y necrosis, caracterizadas por alteración del potencial de membrana mitocondrial. Por otra parte, se observaron elevados porcentajes en la biodisponibilidad de BEA y FUS en las células Caco-2, siendo la FUS la más biodisponibles. La bioaccesibilidad de las ENs, mediante el modelo simulado de digestión in vitro, disminuyó siguiendo el orden: EN A=EN B1>EN B>EN A1. Los datos in vitro obtenidos en esta tesis pueden incorporarse a los datos de toxicidad de BEA, EN y FUS disponibles en la literatura y contribuir, junto a los datos in vivo, a su evaluación del riesgo.Fusarium spp. can produce hexadepsipeptidic mycotoxins, such as beauvericin (BEA) and enniatins (ENs) and the isoprenoidic fusaproliferin (FUS), which occurr naturally in food and feed. In the last decades they showed a potential toxicity to human and animal health, so far there are few data on their toxicity. The objectives of the study were to evaluate the cytotoxic effects of FUS, BEA and ENs A, A1 , B and B1 in Caco-2, CHO-K1 and HT-29 cells, the cytotoxic effects of ENs in combination, the generation of reactive oxygen species (ROS); the production of lipid peroxidation (LPO) after exposure to FUS, BEA and ENs in Caco-2 cells; the cytoprotection of glutathione (GSH) and some polyphenols against the cytotoxicity of ENs and BEA in the Caco-2 and CHO-K1 cells; the effect on the cell cycle, apoptosis/necrosis and mitochondrial membrane potential; the genotoxic effects after exposure to BEA and ENs in Caco-2 cells; BEA and FUS bioavailability by using Caco-2 cells and the bioavailability of ENs A, A1, B and B1 from artificially contaminated grain. BEA and ENs A, A1, B and B1 are cytotoxic in a dose and time-dependent manner in Caco-2, HT-29 and CHO-K1 cells. CHO-K1 and Caco-2 cells were more sensitive to the ENs in group B and group A, respectively. FUS had no cytotoxic effect in the concentrations tested. Synergistic effect was obtained after exposure to the combinations of ENs A1+B, A1+B1, A+A1+B1. Antagonism was produced by the combination of ENs B+B1 at low concentrations, in Caco-2 cells. Oxidative stress was observed after exposure to BEA and ENs in Caco-2 cells in the order: EN A1=EN A>EN B1>BEA>EN B. As a result of oxidative damage LPO occurred in the order: BEA>EN A>EN A1=EN B1>EN B. FUS did not produce any oxidative damage. BEA reduced GSH levels and increased oxidized glutathione (GSSG) levels in Caco-2 cells and polyphenols showed cytoprotective effect in CHO -K1 (t-pterostilbene > myricetin > rutin > quercetin 3-β-glucoside > quercetin) against ENs induced cytotoxicity. BEA and ENs arrested the cell cycle at G2/M phase, which is related to the oxidative imbalance induced by BEA and DNA damage induced by ENs A and A1 in Caco-2 cells. Apoptosis and necrosis were induced and characterized by the mitochondrial membrane potential alteration. High percentages of BEA and FUS bioavailability were determined through Caco-2 cells. FUS was more bioavailable than BEA. ENs bioaccessibility was reduced after applying the in vitro digestion method, in the order: EN A=EN B1>EN B>EN A1. In vitro data obtained in this research work can be incorporated into the whole data related to the cytotoxicity of BEA, EN and FUS in literature and, together with in vivo studies, could contribute to a future risk assessment of them

ACCIDENTAL FALLS AND IMBALANCE IN MULTIPLE SCEROSIS: DIAGNOSTIC CHALLENGES, NEUROPATHOLOGICAL FEATURES, AND TREATMENT STRATEGIES

Lack of balance is common in Multiple Sclerosis (MS) and is among the most disabling symptoms, since it reduces mobility and independence, leads to falls and injuries, and impacts upon overall quality of life. In this research we aimed to report the efforts made to: (i) establish an objective and reliable method to measure imbalance in MS by means of static posturography; (ii) estimate the role of this method in predicting patients at risk of falls; (iii) investigate the neuropathological features leading to imbalance in MS by combining static posturography and conventional / non-coventional magnetic resonance imaging; (iv) verify the effectiveness of visuo-proprioceptive rehabilitation in reducing balance deficit and risk of falls in these patients

Microarray gene expression profiling of neural tissues in bovine spastic paresis

Abstract: Background: Bovine Spastic Paresis (BSP) is a neuromuscular disorder which affects both male and female cattle. BSP is characterized by spastic contraction and overextension of the gastrocnemious muscle of one or both limbs and is associated with a scarce increase in body weight. This disease seems to be caused by an autosomal and recessive gene, with incomplete penetration, although no genes clearly involved with its onset have been so far identified. We employed cDNA microarrays to identify metabolic pathways affected by BSP in Romagnola cattle breed. Investigation of those pathways at the genome level can help to understand this disease. Results: Microarray analysis of control and affected individuals resulted in 268 differentially expressed genes. These genes were subjected to KEGG pathway functional clustering analysis, revealing that they are predominantly involved in Cell Communication, Signalling Molecules and Interaction and Signal Transduction, Diseases and Nervous System classes. Significantly enriched KEGG pathway's classes for the differentially expressed genes were calculated; interestingly, all those significantly under-expressed in the affected samples are included in Neurodegenerative Diseases. To identify genome locations possibly harbouring gene(s) involved in the disease, the chromosome distribution of the differentially expressed genes was also investigated. Conclusions: The cDNA microarray we used in this study contains a brain library and, even if carrying an incomplete transcriptome representation, it has proven to be a valuable tool allowing us to add useful and new information to a poorly studied disease. By using this tool, we examined nearly 15000 transcripts and analysed gene pathways affected by the disease. Particularly, our data suggest also a defective glycinergic synaptic transmission in the development of the disease and an alteration of calcium signalling proteins. We provide data to acquire knowledge of a genetic disease for which literature still presents poor results and that could be further and specifically analysed in the next future. Moreover this study, performed in livestock, may also harbour molecular information useful for understanding human diseases

Multiple sclerosis: changes in microarchitecture of white matter tracts after training with a video game balance board

Purpose: To determine if high-intensity, task-oriented, visual feedback training with a video game balance board (Nintendo Wii) induces significant changes in diffusion-tensor imaging (DTI) parameters of cerebellar connections and other supratentorial associative bundles and if these changes are related to clinical improvement in patients with multiple sclerosis.Conclusion: Despite the low statistical power (35%) due to the small sample size, the results showed that training with the balance board system modified the microstructure of superior cerebellar peduncles. The clinical improvement observed after training might be mediated by enhanced myelinationrelated processes, suggesting that high-intensity, taskoriented exercises could induce favorable microstructural changes in the brains of patients with multiple sclerosis.Materials and Methods: The protocol was approved by local ethical committee; each participant provided written informed consent. In this 24-week, randomized, two-period crossover pilot study, 27 patients underwent static posturography and brain magnetic resonance (MR) imaging at study entry, after the first 12-week period, and at study termination. Thirteen patients started a 12-week training program followed by a 12-week period without any intervention, while 14 patients received the intervention in reverse order. Fifteen healthy subjects also underwent MR imaging once and underwent static posturography. Virtual dissection of white matter tracts was performed with streamline tractography; values of DTI parameters were then obtained for each dissected tract. Repeated measures analyses of variance were performed to evaluate whether DTI parameters significantly changed after intervention, with false discovery rate correction for multiple hypothesis testing.Results: There were relevant differences between patients and healthy control subjects in postural sway and DTI parameters (P <.05). Significant main effects of time by group interaction for fractional anisotropy and radial diffusivity of the left and right superior cerebellar peduncles were found (F2,23 range, 5.555-3.450; P = .036-.088 after false discovery rate correction). These changes correlated with objective measures of balance improvement detected at static posturography (r = 20.381 to 0.401, P < .05). However, both clinical and DTI changes did not persist beyond 12 weeks after training

Efficacy and tolerability of pregabalin as preventive treatment for migraine: a 3-month follow-up study

Migraine is a common neurological disorder and epidemiological studies have documented its high social and economic impact. Unfortunately, preventive treatment is often insufficient to substantially reduce migraine frequency or it is not well tolerated. Antiepileptic drugs are increasingly used in migraine prevention. However, data on efficacy and tolerability of pregabalin in patients with migraine are still lacking. Our aim was to evaluate efficacy and tolerability of pregabalin in patients with migraine. We recruited 47 patients who started pregabalin at 75 mg/day, which was titrated to 300 mg/day as tolerated. A total of six patients (13%) reported one or more side effects during the intake of pregabalin; however, three of them discontinued pregabalin, because side effects were intolerable and persistent. Statistically significant reduction in migraine frequency compared to baseline (p < 0.001) was evident after 1 and 3 months of treatment. A greater frequency reduction was observed in those patients who increased the dosage within the first month of therapy. Our data suggest that pregabalin may be well tolerated and may represent an alternative preventive treatment in migraneurs. Limitations of the present study were a small sample size and an uncontrolled, open-label design; further randomized case–control studies are warranted to confirm our findings

A Case Report of a Woman Affected with Rapid Cycling Bipolar Disorder I and Methabolic Syndrome Improved with Aripiprazole Monotherapy

Introduction We present the case of a 51-years-old Caucasian woman with Bipolar Disorder I (BDI), treated for a long time with typical antipsychotics and mood stabilizers. She referred to our outpatient service because she wished to revise her precriptions, which had caused several side-effects, including metabolic syndrome, gain of body weight, sedation, cognitive impairments, and extrapiramidal symptoms. Moreover, treatment was poorly effective, the patient's compliance was lacking and she experienced frequent relapses. Aims We started treating the patient with aripiprazole at a daily dose of 15 mg. Our aim is to describe the substantial clinical and metabolic improvements of a patient who poorly responded to previous prescriptions. Methods Psychometric measures for the assessment of mood and social functioning were administered at baseline and at the follow-up interviews. Body Mass Index was monitored and blood tests were performed to evaluate the lipid profile (LDL, HDL, total cholesterol, triglycerides), blood glucose, and glycated haemoglobin. Results In the last two years the patient has regularly taken her therapies and attended to follow-up visits. Her social functioning and tolerance to stressful situations have improved, as well as her metabolic profile. Noteworthy, she had not needed further hospitalizations. Conclusions Our clinical observations support the efficacy of aripiprazole in the treatment of BDI. Switching to aripiprazole should be considered in cases similar to the one we have described, characterized by poor compliance, obesity or metabolic syndrome, sensitivity to manifest extrapiramidal syndrome (especially tardive dyskinesia) and other side effects such as sedation and cognitive impairments