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

K Index in cerebrospinal fluid: a valid tool in multiple sclerosis diagnosis

Detection of oligoclonal IgG bands in cerebrospinal fluid by isoelectrocfocusing and immunodetection is the current gold standard to detect an inflammatory process in the central nervous system. It has been proposed that the presence of free light chains (FLCs) in CSF was associated with recent demyelination activity in MS and might be used as a prognosis marker. Our study’s objective is assessing the diagnostic accuracy of a new highly sensitive latex-enhanced nephelometric assay for k free light chain (kFLC) determination in CSF/serum as an alternative to traditional tests and its clinical application. Methods. kFLCs were measured in CSF/serum pairs from 80 patients by the use of a new highly sensitive latex-enhanced nephelometric automated immunoassay for detection of immunoglobulin FLC. The eighty patients were split into three groups according to the neurological diagnosis. In this study we confirm even more the use of the k Index as a diagnostic aid in multiple sclerosis. Results. kFLC Index seems to be more accurate parameter respect the determination of oligoclonal immunoglobulin bands (OCBs). We recalculate the K Index sensitivity and specificity respect the precedent published result. Two patients previously diagnosed with leukoencephalopathy have gone to group 3 as confirmed the diagnosis of MS. Conclusions. These new data reinforce even more the use of the k Index to diagnose MS in comparison to classical methods and to the reference method, the OCBs

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)

Improving cuff-less continuous blood pressure estimation with linear regression analysis

In this work, the authors investigate the cuff-less estimation of continuous BP through pulse transit time (PTT) and heart rate (HR) using regression techniques, which is intended as a first step towards continuous BP estimation with a low error, according to AAMI guidelines. Hypertension (the 'silent killer') is one of the main risk factors for cardiovascular diseases (CVDs), which are the main cause of death worldwide. Its continuous monitoring can offer a valid tool for patient care, as blood pressure (BP) is a significant indicator of health and, using it together with other parameters, such as heart and breath rates, could strongly improve prevention of CVDs. The novelties introduced in this work are represented by the implementation of pre-processing and by the innovative method for features research and features processing to continuously monitor blood pressure in a non-invasive way. Currently, invasive methods are the only reliable methods for continuous monitoring, while non-invasive techniques measure the values every few minutes. The proposed approach can be considered the first step for the integration of these types of algorithms on wearable devices, in particular on those developed for the SINTEC project

Reinforcement learning in populations of spiking neurons

Population coding is widely regarded as a key mechanism for achieving reliable behavioral responses in the face of neuronal variability. But in standard reinforcement learning a flip-side becomes apparent. Learning slows down with increasing population size since the global reinforcement becomes less and less related to the performance of any single neuron. We show that, in contrast, learning speeds up with increasing population size if feedback about the populationresponse modulates synaptic plasticity in addition to global reinforcement. The two feedback signals (reinforcement and population-response signal) can be encoded by ambient neurotransmitter concentrations which vary slowly, yielding a fully online plasticity rule where the learning of a stimulus is interleaved with the processing of the subsequent one. The assumption of a single additional feedback mechanism therefore reconciles biological plausibility with efficient learning

Chromatographic determination of 12 dyes in meat products by HPLC-UV-DIODE array detection

The use of food dyes in meat is regulated by the current European and non-European legislation, due to several food safety concerns. A reliable method for the quali-quantitative determination of 12 food dyes (Amaranth, Ponceau 4R, Carmine, Ponceau SX, Ponceau 3R, Allura Red AC, Carmoisine, Erythrosine, Sudan I, Sudan II, Sudan III and Sudan IV) in meat products, by high performance liquid chromatography coupled to UV diode array detection is presented. The extraction was accomplished by using acetonitrile, methanol, water, and ammonia, 50:40:9:1 (v/v/v/v) as the solvent and ultrasonic bath. The chromatographic separation was obtained with a C18 RP column eluted by a gradient of acetate buffer/acetonitrile. Good analytical performances characterized this method (Table 1), in terms of selectivity, sensitivity, accuracy and ruggedness. Both method precision (CV% range: 6%-15%) and recovery percentages (range: 86%-105%) resulted in compliance with Decision 2002/657/EC, and the expanded measurement uncertainties, estimated by a bottom-up approach, were in the range 6%-20%. All these results demonstrated that the procedure can be applied successfully for confirmation analyses of commercial meat products. •12 food dyes were determined in meat by new HPLC/UV-DAD method.•The analytical method was fully validated for accurate confirmation analyses.•Method accuracy, sensitivity, selectivity and ruggedness resulted satisfactory

Varicella zoster virus and influenza vaccine antibody titres in patients from MAGNIFY-MS who were treated with cladribine tablets for highly active relapsing multiple sclerosis

Lette

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

Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis

Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP) induction was favored over long-term depression (LTD) in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β) perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS

RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis

BACKGROUND: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. OBJECTIVE: To assess the role of RANTES in the regulation of cortical excitability. METHODS: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. RESULTS: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. CONCLUSION: RANTES correlates with inflammation and synaptic excitability in MS brains