1,701 research outputs found
The Link Among Neurological Diseases: Extracellular Vesicles as a Possible Brain Injury Footprint
Extracellular vesicles (EVs), referred as membranous vesicles released into body fluids from all cell types, represent a novel model to explain some aspects of the inter-cellular cross talk. It has been demonstrated that the EVs modify the phenotype of target cells, acting through a large spectrum of mechanisms. In the central nervous system, the EVs are responsible of the wide range of physiological processes required for normal brain function and neuronal support, such as immune signaling, cellular proliferation, differentiation, and senescence. Growing evidences link the EV functions to the pathogenic machinery of the neurological diseases, contributing to the disease progression and spreading. Extracellular vesicles are involved in the brain injury by multimodal ways; they propagate inflammation across the blood brain barrier (BBB), mediate neuroprotection and modulate regenerative processes. For these reasons, extracellular vesicles represent a promising biomarker in neurological disorders as well as an interesting starting point for the development of novel therapeutic strategies. Herein, we review the role of the EVs in the pathogenesis of neurological disease, discussing their potential clinical applications
Investigation of fennel protein extracts by shot-gun Fourier transform ion cyclotron resonance mass spectrometry
A rapid shot-gun method by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) is proposed for the characterization of fennel proteins. After enzymatic digestion with trypsin, few microliters of extract were analyzed by direct infusion in positive ion mode. A custom-made non-redundant fennel-specific proteome database was derived from the well-known NCBI database; additional proteins belonging to recognized allergenic sources (celery, carrot, parsley, birch, and mugwort) were also included in our database, since patients hypersensitive to these plants could also suffer from fennel allergy. The peptide sequence of each protein from that derived list was theoretically sequenced to produce calculated m/z lists of possible m/z ions after tryptic digestions. Then, by using a home-made Matlab algorithm, those lists were matched with the experimental FT-ICR mass spectrum of the fennel peptide mixture. Finally, Peptide Mass Fingerprint searches confirmed the presence of the matched proteins inside the fennel extract with a total of 70 proteins (61 fennel specific and 9 allergenic proteins)
Synthesis of Atropisomeric Hydrazides by One-Pot Sequential Enantio- and Diastereoselective Catalysis
The first catalytic enantioselective and diastereoselective synthesis of atropisomeric hydrazides was achieved using a sequential catalysis protocol. This strategy is based on a one-pot sequence of two organocatalytic cycles featuring the enamine amination of branched aldehydes followed by nitrogen alkylation under phase-transfer conditions. The resulting axially chiral hydrazides were obtained directly from commercially available reagents in high yields and with good stereocontrol. The permutation of organocatalysts allowed easy access to all stereoisomers, enabling a stereodivergent approach to enantioenriched atropisomeric hydrazides
Multiple sclerosis patients treated with cladribine tablets: expert opinion on practical management after year 4
Multiple sclerosis (MS) is a chronic, progressive neurological disease involving neuroinflammation, neurodegeneration, and demyelination. Cladribine tablets are approved for immune reconstitution therapy in patients with highly active relapsing–remitting MS based on favorable efficacy and tolerability results from the CLARITY study that have been confirmed in long-term extension studies. The approved 4-year dosing regimen foresees a cumulative dose of 3.5 mg/kg administered in two cycles administered 1 year apart, followed by 2 years of observation. Evidence on managing patients beyond year 4 is scarce; therefore, a group of 10 neurologists has assessed the available evidence and formulated an expert opinion on management of the growing population of patients now completing the approved 4-year regimen. We propose five patient categories based on response to treatment during the first 4-year regimen, and corresponding management pathways that envision close monitoring with clinical visits, magnetic resonance imaging (MRI) and/or biomarkers. At the first sign of clinical or radiological disease activity, patients should receive a highly effective disease-modifying therapy, comprising either a full cladribine regimen as described in regulatory documents (cumulative dose 7.0 mg/kg) or a comparably effective treatment. Re-treatment decisions should be based on the intensity and timing of onset of disease activity, clinical and radiological assessments, as well as patient eligibility for treatment and treatment preference
An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease
Peripheral markers in Parkinson’s disease (PD) represent a hot issue to provide early diagnosis and assess disease progression. The gold standard marker of PD should feature the same reliability as the pathogenic alteration, which produces the disease itself. PD is foremost a movement disorder produced by a loss of nigrostriatal dopamine innervation, in which striatal dopamine terminals are always markedly reduced in PD patients to an extent, which never overlaps with controls. Similarly, a reliable marker of PD should possess such a non-overlapping feature when compared with controls. In the present study, we provide a novel pathological hallmark, the autophagosome, which in each PD patient was always suppressed compared with each control subject. Autophagosomes were counted as microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive vacuoles at ultrastructural morphometry within peripheral (blood) blood mononuclear cells (PBMC). This also provides the gold standard to assess the autophagy status. Since autophagy may play a role in the pathogenesis of PD, autophagosomes may be a disease marker, while participating in the biology of the disease. Stoichiometric measurement of α-synuclein despite significantly increased in PD patients, overlapped between PD and control patients. Although the study need to be validated in large populations, the number of autophagy vacuoles is neither related with therapy (the amount was similarly suppressed in a few de novo patients), nor the age in PD or controls
The MoxFo initiative-Mechanisms of action: Biomarkers in multiple sclerosis exercise studies
background: as exercise exerts neurobiological and immunomodulatory effects, it might also act as a disease-modifying intervention in MS. however, a clear mechanistic link between exercise and disease-modifying effects in MS has yet to be established.objective: establish recommendations for future mechanistic exercise studies in MS.Methods: In regular meetings, members of the mechanisms of action group within the MoXFo (Moving eXercise research Forward in MS) initiative evaluated gaps of knowledge and discussed unmet needs in mechanistic MS research.results: we concluded that biomarkers assessed in translational studies in humans and animals are essential to decipher the underlying mechanisms of exercise in MS. consequently, we defined clear definitions of different types of biomarkers examined in MS exercise studies and operationalized their use to align with the research question and optimal testing time points. Furthermore, we provide key considerations to improve the rigor of translational studies and defined minimal reporting criteria for animal studies.conclusion: the resulting recommendations are intended to improve the quality of future mechanistic exercise studies in MS and consequently lead to a better understanding of therapeutic approaches
On the Nature of the Rotational Energy Barrier of Atropisomeric Hydrazides
N-N atropisomers represent a useful class of compounds that has recently received important attention from many research groups. This article presents an in-depth analysis of the energy barrier needed for the racemization process of atropoisomeric hydrazides, combining an experimental and computational approach. The focus is on examining how electronic and steric factors impact the racemization process. The results obtained indicate that the barrier observed during the racemization process mainly arises from an increase in the p-orbital character of the nitrogen atoms
Cerebellar control of cortico-striatal LTD
Purpose: Recent anatomical studies showed the presence of cerebellar and basal ganglia connections. It is thus conceivable that the cerebellum may influence the striatal synaptic transmission in general, and synaptic plasticity in particular.
Methods: In the present neurophysiological investigation in brain slices, we studied striatal long-term depression (LTD), a crucial form of synaptic plasticity involved in motor learning after cerebellar lesions in rats.
Results: Striatal LTD was fully abolished in the left striatum of rats with right hemicerebellectomy recorded 3 and 7 days following surgery, when the motor deficits were at their peak. Fifteen days after the hemicerebellectomy, rats had partially compensated their motor deficits and high-frequency stimulation of excitatory synapses in the left striatum was able to induce a stable LTD. Striatal plasticity was conversely normal ipsilaterally to cerebellar lesions, as well as in the right and left striatum of sham-operated animals.
Conclusions: These data show that the cerebellum controls striatal synaptic plasticity, supporting the notion that the two structures operate in conjunction during motor learning
Optimizing the "Time to pregnancy" in women with multiple sclerosis: the OPTIMUS Delphi survey
Background: The debate on how to manage women affected by multiple
sclerosis (MS) during reproductive age is still open, as is the issue of fertility in such
patients. Main issue regard the identification of the optimal window for pregnancy
and how to deal with medical therapy before and during conception. The aim of
this Delphi consensus was to collect the opinions of a multidisciplinary group,
involving reproductive medicine specialists and neurologists with experience in
the management of multiple sclerosis women with reproductive desire.
Methods: Four experts plus scientific coordinators developed a questionnaire
distributed online to 10 neurologists and later discussed the responses and
amended a list of statements. The statements were then distributed via an online
survey to 23 neurologists (comprising the first 10), who voted on their level of
agreement/disagreement with each statement. Consensus was achieved if
agreement or disagreement with a statement exceeded 66%.
Results: Twenty-one statements reached consensus after two rounds of voting,
leading to the following main recommendations: (1) Fertility evaluation should
be suggested to wMS, in case of the need to shorten time to pregnancy and before
treatment switch in women on DMTs contraindicated in pregnancy, particularly in
case of highly active disease and age > 35 years. (2) ART should not be discouraged
in wMS, but the use of DMTs until pregnancy confirmation should be suggested;
ART may be considered in order to reduce time to pregnancy in MS women with
a reduced ovarian reserve and/or age > 35 years, but in case of an expected poor
ART prognosis and the need for more than one ART cycle, a switch to a highefficacy DMD before ART should be offered. (3) Oocyte cryopreservation may
be considered in women with reduced ovarian reserve, with unpredictable time
to complete diagnostic workup and achieve disease control; a risk/cost–benefit
analysis must be performed in women >35 years, considering the diminished
ovarian reserve.
Conclusion: This consensus will help MS neurologists to support family planning
in wMS, respecting MS therapeutic needs while also taking into account the safety
and impact of advancing age on fertility
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