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Exploring novel therapeutic strategies for the treatment of epilepsy-associated neuroinflammation
No full textL'epilessia del lobo temporale mesiale (mesial temporal lobe epilepsy, mTLE) è una delle forme più comuni di epilessia ed è spesso accompagnata da diverse comorbidità che possono avere un impatto significativo sulla qualità della vita. Spesso la mTLE ha origine da un evento traumatico seguito poi da epilettogenesi, processo durante il quale si verificano molteplici fenomeni fisiopatologici, inclusa la neuroinfiammazione. Le stesse crisi epilettiche possono indurre neuroinfiammazione e le crisi ricorrenti spontanee (sponatneous recurrent seizures, SRSs) possono causare una neuroinfiammazione cronica. Una neuroinfiammazione preesistente può inoltre anche aumentare la predisposizione alle crisi, con alterazioni dell'eccitabilità neuronale e peggioramento della neuropatologia. In queste condizioni, sia gli astrociti che le cellule microgliali aumentano lo stato infiammatorio creando un ambiente sfavorevole per le cellule neuronali, con conseguente perdita di contatti sinaptici e morte neuronale.
Durante il mio dottorato di ricerca ho voluto indagare le possibili strategie terapeutiche per il trattamento della neuroinfiammazione associata all'epilessia:
Esplorare l'ipotesi che il 7,8 diidrossiflavone (7,8-DHF), un agonista del recettore BDNF-trkB con effetti antinfiammatori, possa influenzare l'epilettogenesi. Per raggiungere questo obiettivo, è stato utilizzato il modello della litio-pilocarpina. L'effetto del 7,8-DHF sull'astrogliosi è stato valutato mediante analisi immunoistochimica di campioni di cervello ex vivo utilizzando l'anticorpo GFAP. Abbiamo scoperto che basse dosi di 7,8-DHF (5 mg/kg) mostrano una chiara (anche se poco significativa) tendenza a ridurre la neuroinfiammazione.
Testare se una combinazione di fattori neurotrofici (FGF-2 e BDNF) può attenuare la neuroinfiammazione, nello specifico la microcitosi, l'astrocitosi e l'espressione di IL-1β. Abbiamo mirato a verificare se l'attenuazione della neuroinfiammazione ottenuta in vivo con BDNF e FGF-2 (Bovolenta et al., 2010) fosse diretta o secondaria ad altri effetti, ad esempio la riduzione della gravità e della frequenza delle crisi ricorrenti spontanee. Per questo obiettivo, abbiamo utilizzato un modello in vitro di neuroinfiammazione indotta da lipopolisaccaride (LPS, 100 ng/ml) in una coltura gliale mista primaria di topo. È stato analizzato il rilascio di citochine e NO. I nostri risultati suggeriscono che l'effetto antinfiammatorio di BDNF e FGF-2 in vivo in un modello di epilessia sia indiretto e probabilmente dovuto a una riduzione della frequenza e della gravità delle crisi.Mesial temporal lobe epilepsy is one of the most common forms of epilepsy which is often accompained by several comorbidities that can significantly impact the quality of life. This often originates from a precipitating event followed by epileptogenesis, in which multiple pathophysiological phenomena occur, including neuroinflammation. Seizures themselves can induce neuroinflammation and spontaneous recurrent seizures (SRSs) can perpetuate chronic neuroinflammation. Moreover, a pre-existing neuroinflammation enhances the pre-disposition to seizures, linked with alterations in the neuronal excitability as well as increased neuropathology induced by seizures. Both astrocytes and microglial cells exacerbate the inflammatory state and create a very unfavourable environment for neuronal cells, resulting in loss of synapses and neuronal death.
During my PhD I aimed to investigate possible therapeutic strategies for the treatment of epilepsy-associated neuroinflammation:
Exploring the hypothesis that 7,8 dihydroxyflavone (7,8- DHF), an agonist of the BDNF-trkB receptor that may also exert anti-inflammatory effects, can impact epileptogenesis. To avail this goal, the lithium-pilocarpine rat model was used. The effect of this compound on astrogliosis was evaluated by immunohistochemical analysis of ex-vivo brain samples using the GFAP antibody. We found that low 7,8- DHF doses (5 mg/kg) display a clear (even if barely significant) tendency to reduce the neuroinflammation.
Testing if a combination of neurotrophic factors (namely FGF-2 and BDNF) can attenuate parameters of neuroinflammation, including microcytosis, astrocytosis, and the expression of IL-1β. We aimed to test if the attenuation of the neuroinflammation obtained in vivo with BDNF and FGF-2 (Bovolenta et al., 2010) was direct or secondary to other effects, for example the reduction in spontaneous recurrent seizures severity and frequency. For this, we have used an in vitro model of neuroinflammation induced by lipopolysaccharide (LPS, 100 ng/ml) in a mouse primary mixed glial culture. The release of cytokines and NO was analysed. Our results suggested that the anti-inflammatory effect of BDNF and FGF-2 in vivo in an epilepsy model was indirect and likely due to a reduction in seizure frequency and severity
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Lack of Direct Effects of Neurotrophic Factors in an In Vitro Model of Neuroinflammation
No full textNeuroinflammation is associated with several neurological disorders including temporal lobe epilepsy. Seizures themselves can induce neuroinflammation. In an in vivo model of epilepsy, the supplementation of brain-derived neurotropic factor (BDNF) and fibroblast growth factor-2 (FGF-2) using a Herpes-based vector reduced epileptogenesis-associated neuroinflammation. The aim of this study was to test whether the attenuation of the neuroinflammation obtained in vivo with BDNF and FGF-2 was direct or secondary to other effects, for example, the reduction in the severity and frequency of spontaneous recurrent seizures. An in vitro model of neuroinflammation induced by lipopolysaccharide (LPS, 100 ng/mL) in a mouse primary mixed glial culture was used. The releases of cytokines and NO were analyzed via ELISA and Griess assay, respectively. The effects of LPS and neurotrophic factors on cell viability were determined by performing an MTT assay. BDNF and FGF-2 were tested alone and co-administered. LPS induced a significant increase in pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and NO. BDNF, FGF-2, and their co-administration did not counteract these LPS effects. Our study suggests that the anti-inflammatory effect of BDNF and FGF-2 in vivo in the epilepsy model was indirect and likely due to a reduction in seizure frequency and severity
Low-dose 7,8-Dihydroxyflavone Administration After Status Epilepticus Prevents Epilepsy Development
No full textTemporal lobe epilepsy often manifests months or even years after an initial epileptogenic insult (e.g., stroke, trauma, status epilepticus) and, therefore, may be preventable. However, no such preventive treatment is currently available. Aim of this study was to test an antioxidant agent, 7,8-dihydroxyflavone (7,8-DHF), that is well tolerated and effective in preclinical models of many neurological disorders, as an anti-epileptogenic drug. However, 7,8-DHF also acts as a TrkB receptor agonist and, based on the literature, this effect may imply an anti- or a pro-epileptogenic effect. We found that low- (5 mg/kg), but not high-dose 7,8-DHF (10 mg/kg) can exert strong anti-epileptogenic effects in the lithium-pilocarpine model (i.e., highly significant reduction in the frequency of spontaneous seizures and in the time to first seizure after status epilepticus). The mechanism of these different dose-related effects remains to be elucidated. Nonetheless, considering its excellent safety profile and antioxidant properties, as well as its putative effects on TrkB receptors, 7,8-DHF represents an interesting template for the development of effective and well-tolerated anti-epileptogenic drugs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01299-4
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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