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Background Aims: Adipose mesenchymal stem cells (ASCs) represent a promising therapeutic approach in inflammatory neurological disorders, including multiple sclerosis (MS). Recent lines of evidence indicate that most biological activities of ASCs are mediated by the delivery of soluble factors enclosed in extracellular vesicles (EVs). Indeed, we have previously demonstrated that small EVs derived from ASCs (ASC-EVs) ameliorate experimental autoimmune encephalomyelitis (EAE), a murine model of MS. The precise mechanisms and molecular/cellular target of EVs during EAE are still unknown., Methods: To investigate the homing of ASC-EVs, we intravenously injected small EVs loaded with ultra-small superparamagnetic iron oxide nanoparticles (USPIO) at disease onset in EAE-induced C57Bl/6J mice. Histochemical analysis and transmission electron microscopy were carried out 48 h after EV treatment. Moreover, to assess the cellular target of EVs, flow cytometry on cells extracted ex vivo from EAE mouse lymph nodes was performed., Results: Histochemical and ultrastructural analysis showed the presence of labeled EVs in lymph nodes but not in lungs and spinal cord of EAE injected mice. Moreover, we identified the cellular target of EVs in EAE lymph nodes by flow cytometry: ASC-EVs were preferentially located in macrophages, with a consistent amount also noted in dendritic cells and CD4+ T lymphocytes., Conclusions: This represents the first direct evidence of the privileged localization of ASC-EVs in draining lymph nodes of EAE after systemic injection. These data provide prominent information on the distribution, uptake and retention of ASC-EVs, which may help in the development of EV-based therapy in MS., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Fabry disease (FD) is a treatable X-linked lysosomal storage disorder caused by GLA gene variants leading to alpha-galactosidase A deficiency. FD is a rare cause of stroke, and it is still controversial whether in stroke patients FD should be searched from the beginning or at the end of the diagnostic workup (in cryptogenic strokes)., Methods: Fabry-Stroke Italian Registry is a prospective, multicentric screening involving 33 stroke units. FD was sought by measuring α-galactosidase A activity (males) and by genetic tests (males with reduced enzyme activity and females) in patients aged 18-60 years hospitalized for TIA, ischemic stroke, or intracerebral hemorrhage. We diagnosed FD in patients with 1) already known pathogenic GLA variants; 2) novel GLA variants if additional clinical, laboratory, or family-derived criteria were present., Results: Out of 1906 patients, we found a GLA variant in 15 (0.79%; 95%CI 0.44-1.29) with a certain FD diagnosis in 3 (0.16%; 95%CI 0.03-0.46) patients, none of whom had hemorrhage. We identified 1 novel pathogenic GLA variant. Ischemic stroke etiologies in carriers of GLA variants were: cardioaortic embolism (33%), small artery occlusion (27%), other causes (20%), and undetermined (20%). Mild severity, recurrence, previous TIA, acroparesthesias, hearing loss, and small artery occlusion were predictors of GLA variant., Conclusion: In this large multicenter cohort the frequency of FD and GLA variants was consistent with previous reports. Limiting the screening for GLA variants to patients with cryptogenic stroke may miss up to 80% of diagnoses. Some easily recognizable clinical features could help select patients for FD screening., Competing Interests: Declaration of competing interest IR received travel grants and speaker's honoraria from Takeda, Sanofi, and Amicus; PN received speaker's honoraria from Takeda, Sanofi, and Amicus; MZ received fees as consultant and advisory board member from Takeda, Sanofi, and Amicus; SS received personal fees as speaker or advisor (Abbott, Allergan-Abbvie, AstraZeneca, Eli Lilly, Lundbeck, Novartis, NovoNordisk, Pfizer, Teva), research grants (Allergan, Novartis, Uriach), and fees for CME/education (Medscape, Neurodiem Ology Medical Education); UA received speaker's fees and honoraria from EISAI; AM received speaker's honoraria and travel grants from Takeda, Sanofi, and Amicus; DI received speaker's honoraria from Takeda. Other authors declared that they have no competing interests for FSIR study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Symptomatic lacunar stroke (LS) and deep intracerebral hemorrhage (dICH) represent the acute manifestations of type 1 cerebral small vessel disease (cSVD). Recently, two studies showed that the risk factor profile of dICH differs from that associated with LS in subjects with biologically plausible cSVD; however, the prognostic predictors after acute manifestations are currently lacking. We aimed to develop a nomogram for individualized prediction of the mortality probability in a cohort of patients with a first-ever acute manifestation of biologically plausible cSVD., Methods: We conducted a retrospective analysis of data collected from consecutive patients with acute symptomatic non-embolic LS or primary dICH. The outcome measure was 3-month mortality. Based on multivariate logistic model, the nomogram was generated., Results: Of the 288 patients who entered into the study for biologically plausible cSVD, 131 (45%) experienced a LS and 157 (55%) a dICH. After multivariate logistic regression, 5 variables remained predictors of mortality to compose the nomogram: dICH (OR:11.36; p=0.001), severe presentation (OR:8.08; p<0.001), age (OR:1.08; p=0.001), glucose (OR:1.23; p=0.003) and creatinine (OR:1.01; p=0.024) at admission were predictors of mortality. The discriminative performance of nomogram assessed by using the area under the receiver operating characteristic curve (AUC-ROC) was 0.898. The model was internally validated by using bootstrap (1000 samples) with AUC-ROC of 0.895 and cross-validation (deleted-d method repeated 1000 times) with AUC-ROC of 0.895., Conclusions: We developed the first nomogram for prediction of the mortality probability in a cohort of patients with a first-ever acute manifestation of biologically plausible cSVD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We assessed whether polymers of N-acetylglucosamine (GlcNAc) have any pathogenetic role in Alzheimer's disease (AD). First, by using specific dyes, we found deposits of polymers of GlcNAc in sporadic but not in familial AD. We found that neurons and microglia exposed to GlcNAc and uridine diphosphate (UDP)-GlcNAc are able to form GlcNAc polymers, which display a significant neurotoxicity in vitro. Moreover, the exposure of organotypic hippocampal cultures to the same compounds led to synaptic impairment with decreased levels of syntaxin and synaptophysin. In addition, acute hippocampal slices treated with GlcNAc/UDP-GlcNAc showed a clear reduction of long-term potentiation of excitatory synapses. Finally, we demonstrated that microglial cells are able to phagocytose chitin particles and, when exposed to GlcNAc/UDP-GlcNAc, show cellular activation and intracellular deposition of GlcNAc polymers that are eventually released in the extracellular space. Taken together, our results indicate that both microglia and neurons produce GlcNAc polymers, which trigger neurotoxicity both directly and through microglia activation. GlcNAc polymer-driven neurotoxicity offers novel pathogenic insights in sporadic AD and new therapeutic options., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background Aims: Adipose-derived mesenchymal stromal cells (ASC) are known to promote neuroprotection and neuroregeneration in vitro and in vivo. These biological effects are probably mediated by paracrine mechanisms. In recent years, nanovesicles (NV) and microvesicles (MV) have been shown to play a major role in cell-to-cell communication. We tested the efficacy of NV and MV obtained from ASC in mediating neuroprotection and neuroregeneration in vitro., Methods: We exposed neuronal cells (both cell line and primary cultures) to oxidative stress in the presence or not of NV or MV., Results: In this experimental setting, we found that low doses of NV or MV protected neurons from apoptotic cell death. We then assessed the neuroregenerative effect of NV/MV in cerebellar slice cultures demyelinated with lysophosphatidylcholine. We observed that low but not higher doses of NV and MV increased the process of remyelination and activated nestin-positive oligodendroglial precursors., Conclusions: Taken together, our data in vitro support the relevance of ASC vesicles as a source of protecting and regenerating factors that might modulate the microenvironment in neuro-inflammatory as well as in neurodegenerative disorders. The present findings may suggest that stromal cell-derived vesicles might represent a potential therapeutic tool, enabling the safe administration of stromal cell effector factors, avoiding the cellular counterpart., (Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Paroxysmal dysarthria-ataxia is a rare neurological condition due to ephaptic transmission, generally appearing in multiple sclerosis patients characterized by stereotyped attacks of slurred speech usually accompanied by ataxia, appearing many times a day. Here we describe a patient with an unusual remitting-relapsing form of Bickerstaff's-like brainstem encephalitis who manifested PDA after a relapse with the involvement of a peculiar region below the red nuclei and benefited from lamotrigine., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A fifty year-old woman died after drowning in a swimming-pool. Rescue and ambulance paramedic teams started resuscitation attempts followed by a medical care helicopter team. Acute haematemesis, mucosal tears and gastric micro perforations occurred, due to the cardiorespiratory resuscitation manoeuvres. Death occurred seven days later due to the cerebral anoxia and multiorgan failure. Forensic investigations excluded possible malpractice during external cardiac massage as responsible for the woman's death, while Judicial Authority considered the death as the consequence of the delayed intervention of the swimming-pool rescue team.

Oligodendrocytes are a major target of the purported autoimmune response in multiple sclerosis (MS) lesions, but little is known about the mechanisms underlying their demise. Despite the expression of proapoptotic receptors, these cells are rarely seen to undergo apoptosis in situ. On the other hand, cytotoxic mediators present in MS lesions, such as tumor necrosis factor-alpha, are known to generate survival signals through the activation of the transcription factors NF-kappaB and c-jun. The aim of this study was to investigate in chronic active and silent MS lesions and control white matter the expression of c-jun, its activating molecule, JNK, as well as NF-kappaB complex and its inhibitor, IkappaB. By immunohistochemistry we found negligible reactivity for these molecules in control white matter and silent MS plaques. In active MS lesions, double-label immunohistochemistry with oligodendrocyte markers showed up-regulation of the nuclear staining for both NF-kappaB and JNK on a large proportion of oligodendrocytes located at the edge of active lesions and on microglia/macrophages throughout plaques. Oligodendrocytes showed no reactivity for IkappaB, which was predominantly confined to the cytoplasm of microglia/macrophages. We hypothesize that activation of these transcriptional pathways may be one mechanism accounting for the paucity of oligodendrocyte apoptosis reported in MS.

In a recent study we found that the efficiency of translation termination could be decreased several hundred fold by altering the local sequence context surrounding stop codons in the yeast Saccharomyces cerevisiae. Suppression of termination was shown to be mediated by near-cognate tRNA mispairing with the termination codon. We have now examined in greater detail how the local sequence context affects the efficiency of translation termination in this organism. Our results indicate that the sequence immediately upstream of the termination codon plays a significant role in determining the efficiency of translation termination. An extended termination sequence (containing the stop codon and the following three nucleotides) was also found to be a major determinant of termination efficiency, with effects attributable to the fourth nucleotide being largely independent of the termination codon. For the UGA and UAA stop codons, the influence of the fourth position on termination efficiency (from most efficient to least efficient termination) was found to be G > U,A > C, while for the UAG codon it was U,A > C > G. These sequence-specific effects on the efficiency of translation termination suggest that polypeptide chain release factor (or another molecule that may play a role in translation termination, such as rRNA) recognizes an extended termination sequence in yeast. A previous study found a statistically significant bias toward certain tetranucleotide sequences (containing the stop codon and the first distal nucleotide) in several organisms. We found that tetranucleotide sequences most frequently used in yeast are among the most efficient at mediating translation termination, while rare tetranucleotide sequences mediate much less efficient termination. Taken together, our results indicate that upstream and downstream components of an extended sequence context act synergistically to determine the overall efficiency of translation termination in yeast.

We investigated, by immunocytochemistry and immune electron microscopy, the immunophenotype, morphology and functional properties of human peripheral nervous system (PNS) macrophages (M phi) under normal and pathological conditions. Endoneurial M phi disclosed an elongated, ramified morphology, with the main processes oriented along the major axis of nerve fibers; they shared several lineage-related and functional markers with monocyte/macrophages and central nervous system (CNS) microglia, including CD4, CR3, CR4 and FcRIII. In addition, basal expression of HLA-DR antigens was exclusively confined to M phi in normal PNS. In the course of unrelated pathological conditions, resident M phi underwent activation with transformation to hypertrophic cells or foamy phagocytes and up-regulation of the markers expressed in normal conditions; new expression of a macrophagic antigen was detected on activated M phi. In different neuropathies, HLA-DR expression was also detected on non-myelin forming Schwann cells with ultrastructural features indicative of denervation. The present results demonstrate that the human PNS is provided with an intrinsic population of immunocompetent and potentially phagocytic M phi, which represent the peripheral counterpart of CNS microglia.