GABA
receptors (GABA
Rs) mediate the majority of fast inhibitory neurotransmission in the brain via synergistic association with the postsynaptic scaffolding protein gephyrin and its interaction ...partners. However, unlike their counterparts at glutamatergic synapses, gephyrin and its binding partners lack canonical protein interaction motifs; hence, the molecular basis for gephyrin scaffolding has remained unclear. In this study, we identify and characterize two new posttranslational modifications of gephyrin, SUMOylation and acetylation. We demonstrate that crosstalk between SUMOylation, acetylation and phosphorylation pathways regulates gephyrin scaffolding. Pharmacological intervention of SUMO pathway or transgenic expression of SUMOylation-deficient gephyrin variants rescued gephyrin clustering in CA1 or neocortical neurons of Gabra2-null mice, which otherwise lack gephyrin clusters, indicating that gephyrin SUMO modification is an essential determinant for scaffolding at GABAergic synapses. Together, our results demonstrate that concerted modifications on a protein scaffold by evolutionarily conserved yet functionally diverse signalling pathways facilitate GABAergic transmission.
For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β ...interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ≥ 2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 β interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 β interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19-0.37) in the azathioprine and 0.39 (95% CI 0.30-0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as β interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 β interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61-0.95) in the azathioprine and 0.69 (95% CI 0.54-0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year. The results of this study indicate that efficacy of azathioprine is not inferior to that of β interferons for patients with relapsing-remitting multiple sclerosis. Considering also the convenience of the oral administration, and the low cost for health service providers, azathioprine may represent an alternative to interferon treatment, while the different side effect profiles of both medications have to be taken into account.
EudraCT 2006-004937-13.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To describe the disruptions in care experienced by persons with Multiple Sclerosis in Italy due to the COVID-19 pandemic and the self-reported impact on their health and wellbeing.
Methods
...A cross-sectional online survey was completed by 2722 persons with Multiple Sclerosis, after Italy instituted a national lockdown in response to the pandemic.
Results
Persons with Multiple Sclerosis reported that the pandemic caused broad disruptions to usual health and social care services, which impacted on their health and wellbeing. Disruptions in care were consistently associated with negative self-reported impacts on the expected progression of the disease, on out-of-pocket expenditure and on carer’s stress. Psychological consequences were associated with interruption to usual psychological support, and concerns about the safety of care delivered in person.
Conclusions
The quality of life of persons with Multiple Sclerosis depends greatly on prompt access to a broad range of health and care services. Negative psychological impacts reported by persons with Multiple Sclerosis with less severe disabilities show that accessible integrated services are crucial for maintenance of their wellbeing. Most persons with Multiple Sclerosis with more severe disability experienced negative impacts on perceived health. Their carers compensating for lack of social input resulted in care overburden. As continuity of care is crucial for persons with Multiple Sclerosis, as well as for persons with chronic conditions in general, strategies must be in place to ensure it is included in future pandemic response plans.
Unexpectedly, Italy was the first Western country to face COVID-19 outbreak, but promptly it was the first one to adopt stringent procedures to stem the spread of infection. The objective of this ...study was to describe the epidemiological situation and comorbidities in Italy, in addition to containment measures and health system and social protection strengthening ones applied in this country.
Available population data were collected, managed, and analysed from the daily reports on COVID-19 published every day, from 1 February to 8 June 2020.
Lombardia, a northern region of Italy, is considered the epicentre for the wave of the infection with the first diagnosed case, but in a few weeks other regions were involved (with Piemonte, Emilia-Romagna, and Veneto covering more than 70% of the Italian total cases). In the European context, after 3 months of containing measures of the sanitary emergency, Italy is the fourth country for the number of total positive cases (with 235,278 total case as at 8 June 2020), after Russia, the United Kingdom, and Spain, whereas it is the second for the number of deaths (with 33,964 deaths as at 8 June 2020), only after the United Kingdom. Regarding incidence, the curve of daily new cases shows an increasing trend up to 22 March 2020 with 6557 new daily cases and then a decreasing trend up to 280 as at 8 June. This turnaround can be explained by the application of national lockdown starting from 9 March and by the following 14 days of incubation of infection. Profiles of subjects at major risk of poor prognosis and death for COVID-19 are elderly (mean age of 80 years) and with three or more comorbidities. These characteristics can partially explain the high lethality rate for coronavirus observed in Italy, which is the European country with the highest share of elderly. In addition, other possible explanations of this high lethality are differences in testing policies among countries that influence the number of asymptomatic or pauci-symptomatic patients diagnosed as coronavirus positive, together with differences in definition and in the way of recording deaths for coronavirus. In the absence of a vaccine, severe nonpharmaceutical interventions (NPIs), including national lockdown, quarantine, social distancing, and use of facial masks, have been applied with success to reduce the virus spread and the burden on the National Health System. In addition to these stringent containment measures to fight the pandemic, other policies have been adopted searching to ensure economic sustainability, social safety, and stability.
Italy was the first Western country with a wide spread of COVID-19, but it was the first one to introduce containment restrictions, tightening them week by week and subjecting the 60 million people living in the country to unprecedented limitations. Many measurements have been adopted by the government, such as lockdown during the early stages of infection and subsequent social distancing and wearing face masks in public areas. Italians were compliant with all the measures ordered by the government and their discipline reflected in the COVID numbers: the curve of daily new cases after a peak at the end of March now shows a consistent decreasing trend up. In this phase of current reduction of virus diffusion, it is crucial to accommodate the need to continue protecting citizens from the risk of infection with the undeferrable, although gradual, restart of the economic and social system. This new scenario requires an active collaboration among all the actors: statutory bodies, employers, civil society, and the third sector.
Multiple Sclerosis Epidemiology in Europe Bezzini, Daiana; Battaglia, Mario A
Advances in Experimental Medicine and Biology,
01/2017, Letnik:
958
Journal Article, Book Chapter
Recenzirano
Odprti dostop
Multiple sclerosis is characterized by a non-homogeneous distribution around the world. Some authors in past described a latitude gradient, with increasing risk from the equator to North and South ...Poles, but this theory is still controversial. Regarding Europe, there are many articles in the literature concerning the epidemiology of this disease but, unfortunately, they are not always comparable due to different methodologies, they do not cover all countries in the continent, and most of them reported data of small areas and rarely at a national level. In 2012 there were 20 national registries that could help to describe the epidemiology of the disease and, in addition, there is an European Register for Multiple Sclerosis that collect data from already existing national or regional MS registries and databases. Another valid alternative to obtain epidemiological data, also at national level, in a routinely and cost-saving way is through administrative data that are of increasing interest in the last years.
Background
The Big Multiple Sclerosis Data (BMSD) network (
https://bigmsdata.org
) was initiated in 2014 and includes the national multiple sclerosis (MS) registries of the Czech Republic, Denmark, ...France, Italy, and Sweden as well as the international MSBase registry. BMSD has addressed the ethical, legal, technical, and governance-related challenges for data sharing and so far, published three scientific papers on pooled datasets as proof of concept for its collaborative design.
Data collection
Although BMSD registries operate independently on different platforms, similarities in variables, definitions and data structure allow joint analysis of data. Certain coordinated modifications in how the registries collect adverse event data have been implemented after BMSD consensus decisions, showing the ability to develop together.
Data management
Scientific projects can be proposed by external sponsors via the coordinating centre and each registry decides independently on participation, respecting its governance structure. Research datasets are established in a project-to-project fashion and a project-specific data model is developed, based on a unifying core data model. To overcome challenges in data sharing, BMSD has developed procedures for federated data analysis.
Future perspectives
Presently, BMSD is seeking a qualification opinion from the European Medicines Agency (EMA) to conduct post-authorization safety studies (PASS) and aims to pursue a qualification opinion also for post-authorization effectiveness studies (PAES). BMSD aspires to promote the advancement of real-world evidence research in the MS field.
Improvement of sensory strategies is a relevant part of balance rehabilitation in multiple sclerosis (MS). This study aimed to Assess the effectiveness of visual-feedback exercises in improving ...balance in MS. We divided 36 patients into Wii and control-treated groups that underwent balance rehabilitation. Outcomes were obtained for Berg Balance Scale (BBS), Modified Fatigue Impact Scale, and sway area under conditions of opened and closed eyes. BBS showed a statistically significant improvement (from 49.6 to 54.6 points, p < 0.05) in the Wii group. Interactive visual-feedback exercises such as Wii could be more effective than the current standard protocol in improving balance disorders in MS.
Upper limb impairments can occur in patients with multiple sclerosis, affecting daily living activities; however there is at present no definite agreement on the best rehabilitation treatment ...strategy to pursue. Moreover, motor training has been shown to induce changes in white matter architecture in healthy subjects.
This study aimed at evaluating the motor behavioral and white matter microstructural changes following a 2-month upper limb motor rehabilitation treatment based on task-oriented exercises in patients with multiple sclerosis.
Thirty patients (18 females and 12 males; age=43.3±8.7years) in a stable phase of the disease presenting with mild or moderate upper limb sensorimotor deficits were randomized into two groups of 15 patients each. Both groups underwent twenty 1-hour treatment sessions, three times a week. The “treatment group” received an active motor rehabilitation treatment, based on voluntary exercises including task-oriented exercises, while the “control group” underwent passive mobilization of the shoulder, elbow, wrist and fingers.
Before and after the rehabilitation protocols, motor performance was evaluated in all patients with standard tests. Additionally, finger motor performance accuracy was assessed by an engineered glove.
In the same sessions, every patient underwent diffusion tensor imaging to obtain parametric maps of fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. The mean value of each parameter was separately calculated within regions of interest including the fiber bundles connecting brain areas involved in voluntary movement control: the corpus callosum, the corticospinal tracts and the superior longitudinal fasciculi.
The two rehabilitation protocols induced similar effects on unimanual motor performance, but the bimanual coordination task revealed that the residual coordination abilities were maintained in the treated patients while they significantly worsened in the control group (p=0.002). Further, in the treatment group white matter integrity in the corpus callosum and corticospinal tracts was preserved while a microstructural integrity worsening was found in the control group (fractional anisotropy of the corpus callosum and corticospinal tracts: p=0.033 and p=0.022; radial diffusivity of the corpus callosum and corticospinal tracts: p=0.004 and p=0.008). Conversely, a significant increase of radial diffusivity was observed in the superior longitudinal fasciculi in both groups (p=0.02), indicating lack of treatment effects on this structure, showing damage progression likely due to a demyelination process.
All these findings indicate the importance of administering, when possible, a rehabilitation treatment consisting of voluntary movements. We also demonstrated that the beneficial effects of a rehabilitation treatment are task-dependent and selective in their target; this becomes crucial towards the implementation of tailored rehabilitative approaches.
•We evaluate the effects of upper limb motor rehabilitation in multiple sclerosis.•We assess motor behavioral and white matter microstructural changes after treatment.•A 2-month treatment including task-oriented exercises improves motor behavior.•White matter integrity in the corpus callosum and corticospinal tracts is preserved.•Beneficial rehabilitation effects are task-dependent and selective in their target.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to ...prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS.
This is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses.
Results will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials.
Andalusia: NCT01745783 , registered on Dec 10, 2012. Badalona: NCT02035514 EudraCT, 2010-024081-21. Registered on 2012. Canada: ClinicalTrials.gov, NCT02239393 . Registered on September 12, 2014. Copenhagen: EudraCT, 2012-000518-13 . Registered on June 21, 2012. Italy: EudraCT, 2011-001295-19, and ClinicalTrials.gov, NCT01854957 . Retrospectively registered on May 16, 2013. London: Eudra CT 2012-002357-35, and ClinicalTrials.gov, NCT01606215 . Registered on May 25, 2012. Salzburg: EudraCT, 2015-000137-78 . Registered on September 15, 2015. Stockholm: ClinicalTrials.gov, NCT01730547 . Registered on November 21, 2012. Toulouse: ClinicalTrials.gov, NCT02403947 . Registered on March 31, 2015.
Motor imagery (MI) is defined as mental execution without any actual movement. While healthy adults usually show temporal equivalence, i.e., isochrony, between the mental simulation of an action and ...its actual performance, neurological disorders are associated with anisochrony. Unlike in patients with stroke and Parkinson disease, only a few studies have investigated differences of MI ability in multiple sclerosis (MS). However, the relationship among disease severity, anisochrony and brain activation patterns during MI has not been investigated yet. Here, we propose to investigate MI in MS patients using fMRI during a behavioral task executed with dominant/non-dominant hand and to evaluate whether anisochrony is associated with disease severity. Thirty-seven right-handed MS patients, 17 with clinically isolated syndrome (CIS) suggestive of MS and 20 with relapsing-remitting MS (RR-MS) and 20 right-handed healthy controls (HC) underwent fMRI during a motor task consisting in the actual or imaged movement of squeezing a foam ball with the dominant and non-dominant hand. The same tasks were performed outside the MRI room to record the number of actual and imagined ball squeezes, and calculate an Index of performance (IP) based on the ratio between actual and imagined movements. IP showed that a progressive loss of ability in simulating actions (i.e., anisochrony) more pronounced for non-dominant hand, was found as function of the disease course. Moreover, anisochrony was associated with activation of occipito-parieto-frontal areas that were more extensive at the early stages of the disease, probably in order to counteract the changes due to MS. However, the neural engagement of compensatory brain areas becomes more difficult with more challenging tasks, i.e., dominant vs. non-dominant hand, with a consequent deficit in behavioral performance. These results show a strict association between MI performance and disease severity, suggesting that, at early stages of the disease, anisochrony in MI could be considered as surrogate behavioral marker of MS severity.
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