1,354,499 research outputs found
The claustrum of the bottlenose dolphin Tursiops truncatus (Montagu 1821)
No full textThe mammalian claustrum is involved in processing sensory information from the environment. The claustrum is reciprocally connected to the visual cortex and these projections, at least in carnivores, display a clear retinotopic distribution. The visual cortex of dolphins occupies a position strikingly different from that of land mammals. Whether the reshaping of the functional areas of the cortex of cetaceans involves also modifications of the claustral projections remains hitherto unanswered. The present topographic and immunohistochemical study is based on the brains of eight bottlenose dolphins and a wide array of antisera against: calcium-binding proteins (CBPs) parvalbumin (PV), calretinin (CR), and calbindin (CB); somatostatin (SOM); neuropeptide Y (NPY); and the potential claustral marker Gng2. Our observations confirmed the general topography of the mammalian claustrum also in the bottlenose dolphin, although (a) the reduction of the piriform lobe modifies the ventral relationships of the claustrum with the cortex, and (b) the rotation of the telencephalon along the transverse axis, accompanied by the reduction of the antero-posterior length of the brain, apparently moves the claustrum more rostrally. We observed a strong presence of CR-immunoreactive (-ir) neurons and fibers, a diffuse but weak expression of CB-ir elements and virtually no PV immunostaining. This latter finding agrees with studies that report that PV-ir elements are rare in the visual cortex of the same species. NPY- and somatostatin-containing neurons were evident, while the potential claustral markers Gng2 was not identified in the sections, but no explanation for its absence is currently available. Although no data are available on the projections to and from the claustrum in cetaceans, our results suggest that its neurochemical organization is compatible with the presence of noteworthy cortical inputs and outputs and a persistent role in the general processing of the relative information. © 2014 Cozzi, Roncon, Granato, Giurisato, Castagna, Peruffo, Panin, Ballarin, Montelli and Pirone
New putative therapeutic targets and biomarkers of epileptogenesis: epigenetic, computational and neurochemical analyses
No full textL’epilessia del lobo temporale (TLE) origina nel sistema limbico del cervello, spesso dopo un periodo di latenza che segue un evento lesionale. Durante la fase di latenza (epilettogenesi) i pazienti stanno apparentemente bene e la diagnosi di epilessia è possibile solamente quando compaiono le crisi. I farmaci antiepilettici ad oggi disponibili sono efficaci per il trattamento dei sintomi (le crisi epilettiche), ma per la cura dell’epilessia. Inoltre, più del 30% dei pazienti affetti da epilessia del lobo temporale diventano resistenti al trattamento farmacologico e, solo per una piccola percentuale di essi, l’unica alternativa è la resezione chirurgica del focus epilettico. L’epilettogenesi è caratterizzata da modificazioni cellulari e molecolari che trasformano un cervello da sano a epilettico. Questi cambiamenti, che avvengono durante la fase di epilettogenesi, includono modifiche “a lungo termine” di espressione genica e alterazioni nel rilascio di neurotrasmettitori, come glutammato e GABA, che portano ad uno sbilanciamento tra eccitazione e inibizione nervosa. In questa tesi, ho studiato il ruolo dei microRNA (miRNA) nella regolazione di meccanismi patogenetici nel giro dentato (DG) isolato con la tecnica della microdissezione laser, in ratti epilettici a diversi time point della malattia e in pazienti farmacoresistenti che si sono sottoposti alla chirurgia. L’analisi microarray ha identificato 64 miRNA differenzialmente espressi in diverse fasi della patologia (latenza precoce e tardiva, al momento della prima crisi spontanea e in fase cronica) nel modello animale della pilocarpina nel ratto. Lo studio comparativo tra i ratti epilettici (in fase cronica) e il giro dentato di pazienti farmacoresistenti ha rivelato una sovrapposizione di 4 miRNA (miR-21-5p, miR-23a5p, miR-146a-5p e miR-181c-5p). Tuttavia, cambiamenti nell’espressione di miRNA nel ratto potrebbero essere modello-specifici e non direttamente riconducibili alla malattia. Quindi, è stata effettuata una meta-analisi di vari set di dati disponibili, ottenuti da DG di animali resi epilettici attraverso l’impiego di diversi modelli di epilessia del lobo temporale. Questa meta-analisi ha identificato la deregolazione di 44 e 8 miRNA, rispettivamente nelle fasi di latenza e cronica. Le alterazioni, così identificate, possono essere considerate malattia-specifiche, piuttosto che direttamente riconducibili al modello animale utilizzato. Inoltre, uno studio istopatologico
combinato ad un’indagine microarray ha rivelato il miR-487a come maggiormente espresso in campioni di pazienti senza patologia dei granuli di tipo 2, un pattern istologico associato una migliore prognosi dopo l’intervento chirurgico. Questi risultati suggeriscono, quindi, un ruolo di miR-487a come biomarcatore nell’identificazione di una corretta prognosi dopo l’intervento del chirurgo. Per approfondire il ruolo dei miRNA come biomrcatori di patologia, uno studio di microarray è stato quindi condotto su campioni di plasma ottenuti da ratti epilettici in tutte le fasi della patologia, evidenziando una significativa up-regolazione di miR9a-3p (miRNA cervello specifico) nella fase di latenza precoce, rivelando grandi potenzialità come biomarcatore di epilettogenesi. Analisi di reti trascrizionali integrate con dati di suscettibilità genetica e informazioni fenotipiche permettono di indagare specifici programmi trascrizionali connessi a diversi stadi della patologia. Un’analisi computazionale effettuata su campioni ottenuti da pazienti affetti da epilessia del lobo temporale, topi resi epilettici con il modello della pilocarpina e zebrafish in cui le “crisi” sono state indotte con pentilentetrazolo ha portato all’identificazione del gene Sestrina 3 (Sesn3) come un trans-regolatore di un network di geni cosiddetti “proconvulsivanti”. Ratti knock out per il gene Sesn3 hanno mostrato un significativo ritardo nel raggiungimento dello stato epilettico dopo la somministrazione di pilocarpina. Inoltre, all’analisi comportamentale è stato osservato un fenotipo meno ansioso con una minore predisposizione allo sviluppo di depressione. Questi risultati suggeriscono un ruolo di Sesn3 come un regolatore genico comune nella comparsa di crisi e di comorbidità associate all’epilessia. L’insorgenza di crisi nella fase cronica della patologia potrebbe essere dovuta ad uno sbilanciamento tra le neurotrasmissioni eccitatoria ed inibitoria nel sistema nervoso centrale. In questa tesi, i livelli di GABA e glutammato sono stati studiati attraverso una microdialisi intra-cranica in animali resi epilettici con il modello della pilocarpina, attraverso diverse fasi della malattia. Si è osservato un significativo peggioramento nel rilascio di GABA a partire dalla prima crisi spontanea, in concomitanza ad una desensibilizzazione dei recettori GABAA. In contrasto, sono stati trovati significativamente alti livelli di glutammato, in ippocampo di ratti epilettici suggerendone un ruolo nel mantenimento della condizione epilettica, nella fase tardiva della malattia. Tutti insieme, i risultati presentati in questa tesi evidenziano un ruolo di specifici miRNA neuronali e Sesn3 come putativi regolatori di meccanismi che possono portare
all’insorgenza dell’epilessia. I miRNA che sono particolarmente rilevanti nella fase di epilettogenesi, potrebbero quindi essere ulteriormente studiati come nuovi bersagli terapeutici per la cura dell’epilessia. Inoltre, alterati livelli plasmatici di miRNA circolanti, nella fase di epilettogenesi, rivelano un grande potenziale di queste molecole a divenire biomarcatori per l’identificazione di quei pazienti che svilupperanno la TLE in seguito ad un insulto cerebrale. Infine, lo studio quei miRNA per i quali i livelli di espressione risultano alterati, e Sesn3, risulta utile per una migliore comprensione di quei meccanismi che sono alla base della formazione delle crisi e della farmacoresistenza nei pazienti affetti. Infatti, l’analisi dei target predetti di questi miRNA ha evidenziato RNA messaggeri coinvolti nella regolazione dei recettori per il GABA e glutammato, i quali sono attori già validati nella patogenesi dell’epilessia.Temporal lobe epilepsy (TLE) arises in the limbic system of the brain, often after a latency period that follows a lesional event. During the latency phase (epileptogenesis) patients are apparently well, and the diagnosis of epilepsy is possible only when seizures begin to occur. Currently available antiepileptic drugs (AEDs) are effective for the treatment of the symptoms (seizures) but not for curing the disease. Furthermore, more than 30% of TLE patients are resistant to pharmacological treatments and, just for a small percentage of them, the only option is the surgical resection of the epileptogenic area. Epileptogenesis is characterized by cellular and molecular modifications that transform a healthy brain in epileptic. The modifications occurring during epileptogenesis include “long-lasting” changes to gene expression and alterations in the release of neurotransmitters, like glutamate and GABA, which lead to an unbalance between excitation and inhibition. In this thesis, I first investigated the role of microRNAs (miRNAs) in regulating pathogenetic mechanisms in the laser-microdissected dentate gyrus (DG) of epileptic rats, at different time points of the disease, and in drug-resistant patients that underwent surgery. Microarray analysis identified 64 miRNAs that are differentially expressed in the different phases of the disease (early and late latency, first spontaneous seizure and chronic stage) in the rat pilocarpine model of epilepsy. The comparison between epileptic rats and human DG revealed an overlap of 4 miRNAs (miR-21-5p, miR-23a-5p, miR-146a-5p and miR-181c-5p). Changes observed in rats, however, may be model specific. A meta-analysis of different available datasets, obtained from the DG of animals made epileptic with different models of TLE, detected the dys-regulation of 44 and 8 miRNAs, respectively in the latency and in the chronic stages. Thus, these altered levels of miRNAs may be considered as diseasespecific rather than model-specific. Moreover, a combinatorial histopathological and miRNAs signature identified miR-487a as highly expressed in human samples without granule cell pathology-type 2, a histological pattern that associates with a better prognosis after surgery. These findings suggest miR-487a as a putative biomarker for establishing the prognosis after surgery. In addition, levels of circulating miRNAs have been studied with a
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Abstract
microarray strategy, highlighting a significant up-regulation of the brain-enriched miR-9a-3p in plasma samples of rats killed in the early latency phase, suggesting its role as a putative biomarker of epileptogenesis. Integrated analysis of transcriptional networks with genetic susceptibility data and phenotypic information allows to connect specific transcriptional programs to disease states. A computational analysis on TLE patients, pilocarpine-treated mice and pentilentetrazoleinduces seizures in zebrafish identified the gene Sestrin 3 (SESN3) as a trans-regulator of a pro-convulsant gene network. SESN3-KO rats shown a significant delay in status epilepticus onset after pilocarpine injection. Moreover, a behavioral analysis of these rats revealed a phenotype less anxious and less prone to depression. These findings suggest a role of SESN3 as a common regulator of seizure onset and of comorbid disorders associated to epilepsy. Seizure onset in the chronic stage of the disease may be due to an unbalance between excitatory and inhibitory neurotransmission. In this thesis, GABA and glutamate levels have been investigated through intra-cranial microdialysis at different phases of the disease in the rat pilocarpine model. The study revealed a significant impairment of GABA release starting with the first spontaneous seizure, when GABA-A receptor desensitization is also observed. In contrast, significantly higher levels of glutamate have been found in the hippocampus of epileptic rats, and may play a role in the maintenance of a chronic epileptic condition. Taken together, the results presented in this thesis suggest a role of specific brainenriched miRNAs and SESN3 as putative epigenetic regulators of mechanisms that can lead to epilepsy. MicroRNAs that are particularly relevant in the phase of epileptogenesis and may be further investigated as novel therapeutic targets for the treatment of epilepsy. Moreover, altered circulating levels of miRNAs in the early stages of latency have great potential for becoming biomarkers to help identifying those patients that will develop epilepsy after a brain lesion. In addition, miRNAs whose expression levels are modified and the gene SESN3 may be helpful for understanding the mechanisms of seizure onset and drugs-resistance. Indeed, analysis of the predicted targets of these miRNAs highlighted their involvement in the regulation of GABA and glutamate receptors that are already established actors in the pathogenesis of epilepsy
Metabolic syndrome and the risk of late onset Alzheimer's disease: An updated review and meta-analysis
No full textAims: This study aims to provide an updated systematic review and meta-analysis on the risk of Alzheimer's disease (AD) in patients with metabolic syndrome (MetS) and to analyze the contribution of each MetS component on AD onset. Data synthesis: The study was performed according to the PRISMA guideline. Data were obtained searching MEDLINE, Scopus, Web of Science, and EMBASE for studies published between January 1, 2010 and July 30, 2020, evaluating the association between MetS and AD risk. A total of 255 articles were retrieved and 6 investigations (4 prospective and 2 retrospective) met the inclusion criteria. Overall, 9.788.021 patients with a mean follow-up of 4.5 years were analyzed. The pooled analysis revealed a slight increased risk of AD in MetS (hazard ratio, HR: 1.10, 95% and confidence interval, CI: 1.05–1.15). Egger's test indicated the absence of publication bias (t = 2.095 and p = 0.104). However, while analysis based on prospective studies failed to show a significant association between MetS and AD (HR: 0.80 and 95% CI: 0.61–1.05), analysis based on retrospective studies demonstrated a significant, slight increased risk (HR:1.11 and 95% CI: 1.08–1.66). With regard to MetS components, the risk was: arterial hypertension, HR: 1.05 (95% CI: 1.04–10.6); hyperglycemia/diabetes, HR: 1.19 (95% CI: 1.18–1.99); low high-density lipoprotein cholesterol (HDL-C), HR: 1.07 (95% CI: 1.06–1.07); hypertriglyceridemia, HR: 1.06 (95% CI: 1.05–1.06); and abdominal obesity, HR: 0.84 (95% CI: 0.74–0.95). Conclusions: We found a significant association between MetS and AD, mainly driven by large retrospective studies. Our data also support the association of single MetS components with AD incidence, while increased waist circumference seems to have a “protective role” probably due to reverse causality
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
No full text“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Paraoxonase-1 (PON-1) Arylesterase Activity Levels in Patients with Coronary Artery Disease: A Meta-Analysis
No full textAim: To review and compare the PON-1 arylesterase activity between coronary artery disease (CAD) and non-CAD patients. Methods: Data were obtained by searching MEDLINE and Scopus for all investigations published between January 1, 2000 and March 1, 2021 comparing PON-1 arylesterase activity between CAD and controls. Results: Twenty studies, based on 5417 patients, met the inclusion criteria and were included in the analysis. A random effect model revealed that PON-1 arylesterase activity was significantly lower in the CAD group compared to controls (SMD = -0.587, 95%CI = -0.776 to -0.339, p < 0.0001, I2 = 92.3%). In CAD patients, the PON-1 arylesterase activity was significantly higher among CAD patients without diabetes mellitus (DM) compared to those with diabetes (SMD: 0.235, 95% CI: 0.014 to 0.456, p = 0.03, I2 = 0%). Conclusions: PON-1 activity is significantly lower in CAD patients, and those without DM presented a significantly higher PON-1 arylesterase activity
Increased extracellular levels of glutamate in the hippocampus of chronically epileptic rats
No full textAn increase in the release of excitatory amino acids has consistently been observed in the hippocampus during seizures, both in humans and animals. However, very little or nothing is known about the extracellular levels of glutamate and aspartate during epileptogenesis and in the interictal chronic period of established epilepsy. The aim of this study was to systematically evaluate the relationship between seizure activity and changes in hippocampal glutamate and aspartate extracellular levels under basal and high K+-evoked conditions, at various time-points in the natural history of experimental temporal lobe epilepsy, using in vivo microdialysis. Hippocampal extracellular glutamate and aspartate levels were evaluated: 24h after pilocarpine-induced status epilepticus (SE); during the latency period preceding spontaneous seizures; immediately after the first spontaneous seizure; in the chronic (epileptic) period. We found that (i) basal (spontaneous) glutamate outflow is increased in the interictal phases of the chronic period, whereas basal aspartate outflow remains stable for the entire course of the disease; (ii) high K+ perfusion increased glutamate and aspartate outflow in both control and pilocarpine-treated animals, and the overflow of glutamate was clearly increased in the chronic group. Our data suggest that the glutamatergic signaling is preserved and even potentiated in the hippocampus of epileptic rats, and thus may favor the occurrence of spontaneous recurrent seizures. Together with an impairment of GABA signaling (Soukupova et al., 2014), these data suggest that a shift toward excitation occurs in the excitation/inhibition balance in the chronic epileptic state
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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