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MRI biomarkers of disease evolution and efficacy of stem cell therapy in the SOD1(G93A) experimental model of Amyotrophic Lateral Sclerosis
No full textLa Sclerosi Laterale Amiotrofica (SLA) è una malattia neurodegenerativa mortale che colpisce i motoneuroni superiori nella corteccia motoria e i motoneuroni inferiori nel tronco cerebrale e del midollo spinale.La diagnosi di SLA rimane ancora oggi una diagnosi ad esclusione di altre patologie perché non vi sono segni clinici patognomonici, soprattutto all’ esordio, nè test diagnostici specifici. La diagnosi viene quindi formulata dopo un’ accurato esame neurologico alla ricerca di segni di lesione, ma sarà poi solo la progressione della malattia e la comparsa di nuovi segni che confermerà la diagnosi nel tempo. Nella SLA, l'assenza di marcatori specifici per la malattia comporta un ritardo tra la comparsa della malattia e la diagnosi che può variare tra i 13 ei 18 mesi, precludendo un inizio precoce dei trattamenti neuroprotettivi.La scoperta delle mutazioni SOD1 legate alla SLA di origine eraditaria ha permesso di sviluppare modelli eziologici per la malattia. Grazie al modello animale SOD1(G93A), modalità di neuroimaging, tra cui la Risonanza Manetica (RM), possono essere utilizzate per identificare potenziali biomarcatori della patologia.Questo progetto di dottorato è diviso in due sezioni sperimentali.La prima parte del progetto ha l'obiettivo di identificare e validare biomarcatori RM in un modello sperimentale di SLA (topi SOD1(G93A)) durante la progressione della malattia e, sucessivamente, di monitorare l'efficacia di una terapia basata sulle cellule staminali.Studi recenti hanno suggerito che la malattia potrebbe iniziare nel muscolo scheletrico, piuttosto che nei motoneuroni. Per questo motivo, il nostro protocollo RM si focalizza sia sul cervello, che sugli arti posteriori degli animali; le immagini RM sono state acquisite a punti temporali corrispondenti al decorso della malattia (fase preclinica, insorgenza e la fase terminale). Immagini T2-pesate, mappe del T2 e le successive analisi con la tecnica Voxel Based Morphometry, hanno mostrato lesioni del tronco cerebrale nei topi a partire dalla comparsa della malattia. L’analisi RM degli arti posteriori ha riportato: riduzione del volume muscolare, alterazione dei parametri DTI (FA, MD e RD) e variazione nel rapporto tra intensità del segnale del muscolo e intensità del segnale del grasso.Testando l'efficacia di una terapia innovativa, attraverso l'evoluzione dei biomarker precedentemente definiti, abbiamo confermato l'efficacia della terapia cellulare nel rallentare il decorso clinico nel modello animale SOD1(G93A).Tuttavia, studi recenti hanno riportato che la maggior parte degli effetti terapeutici delle cellule staminali sono probabilmente duvuti a fattori solubili rilasciati in nanovescicole (esosomi). Per capire meglio come e dove gli esosomi esplicano il loro effetto terapeutico, si ha bisogno comprendere il loro meccanismo d’ azione e i loro bersagli molecolari/cellulari. La RM può essere utilizzata come metodo non invasivo per la visualizzazione degli esosomi e può fornire informzioni su dove gli esosomi esercitano la loro azione neuroportettiva.Nella seconda parte del progetto, noi proponiamo un nuovo approccio per marcare gli esosomi con nanoparticelle di ossido di ferro (USPIO), permettendo la loro individuazione attraverso immagini RM. Inoltre, questo nuovo metodo di labeling preserva le caratteristiche morfologiche e fisiologiche degli esosomi. In particolare, abbiamo dimostrato che marcando le cellule staminali con le USPIO prima dell’ estrazione degli esosomi, questi, una volta isolati, trattengono le nanoparticelle e possono essere visualizzati tramite RM, sia in vitro che in vivo.Amyotrophic lateral sclerosis (ALS) is fatal neurodegenerative disorder affecting upper motor neurons in the motor cortex as well as lower motor neurons in the brain stem and spinal cord. In ALS, the absence of a disease marker has a negative consequence: the delay from onset of the disease to diagnosis can vary between 13 and 18 months precluding early initiation of neuroprotective treatments. The capability of Magnetic Resonance Imaging (MRI) in diagnosis of ALS has been recently addressed. The accessible, non-invasive and radiation-free characteristics of MRI make this technique highly practical as a biomarker tool. MRI has been used in ALS patients, but not during the pre-clinical phase, a stage currently inaccessible for human study in what is largely a sporadic disease. The discovery of SOD1 mutations linked with familial ALS has made it possible to develop aetiological models for ALS. Thanks to the SOD1(G93A) animal model, neuroimaging modalities can be used to identify potential biomarkers. This PhD project is divided in two experimental sections.The first section aimed to identify and validate MRI biomarkers in SOD1(G93A) animal model along the disease progression and to monitor the efficacy of stem cells-based therapy. Recent studies have suggested that the disease could initiate in skeletal muscle, rather than in the motor neurons. For this reason, our MRI protocol focused on brain and hind limb and SOD1(G93A) mice were scanned at time point corresponding to disease evolution (preclinical stage, onset and terminal stage). T2-weighted images, T2 map and the subsequent analysis with Voxel Based Morphometry technique, showed brainstem lesions in mice starting from the onset of the disease. In hind limb of SOD1(G93A) we found reduced muscular volume, alteration in Diffusion Tensor Imaging parameters (FA, MD and RD) and in muscle/fat signal intensity ratio. Testing the efficacy of innovative therapy, through the evolution of the previously defined biomarkers, we confirmed the efficacy of stem cells therapy in slowing down the clinical course in the SOD1(G93A) animal model.However, recent studies reported that most biological effects of stem cells are probably mediated by soluble factors released in nanovescicles (exosomes) which influence the surrounding cells. To better understand the action mechanisms and the molecular/cellular target of exosomes, we need elucidation of where exosomes explicate their therapeutic effect. In particular, MRI can be used as a noninvasive method for tracking exosomes in vivo and it can provide information about where exosomes exert their neuroprotective action. In the second section we propose a new approach to label exosomes with iron oxide nanoparticles that allows their detection by MRI preserving their morphology and physiological characteristic. In particular, we showed that by labeling stem cells with ultra-small superparamagnetic iron oxide nanoparticles before nanovesicles extraction, the isolated exosomes retain nanoparticles and can be visualized by MRI both in in vitro and in vivo condition
Comparative technical analysis of lipoaspirate mechanical processing devices
No full textFat grafting is a well-established procedure in reconstructive, aesthetic, and regenerative medicine, in particular due to the presence in the adipose tissue of a high concentration of mesenchymal stem cells. The need to reduce fat processing times, for an immediate clinical use and regulatory restrictions on the degree of manipulation of human tissues have led to the development of numerous devices for the mechanical, non-enzymatic processing of adipose tissue. The aim of this study is to describe the state of the art of mechanical devices used for fat processing, performing a technical analysis of the currently commercially available devices. This should facilitate the development of new devices that improve therapeutic results
Imaging the pH evolution of an acute kidney injury model by means of iopamidol, a MRI-CEST pH-responsive contrast agent.
No full textPurpose To investigate in vivo possible pH level alterations following an acute renal failure disease using a MRI-CEST pH responsive contrast agent. The impact of functional evolution in different renal compartments over time was also investigated. Methods a mouse model of acute kidney injury was obtained by glycerol-induced rhabdomyolysis. pH maps were obtained using Iopamidol (0.75 g iodine/kg b.w. corresponding to 2.0 mmol/kg) in a control group (n = 3) and in the acute kidney injury group (n = 6) at 1, 3, 7, 14, and 21 days after the damage induction at 7T. Histology assessment of renal damage and blood urea nitrogen levels were compared with pH maps. Results during the acute kidney injury, there was a robust increase of pH values, which peaked after 3 days, compared with the predamage situation. In addition, it was possible to detect changes in contrast detection between the different functional regions of the damaged kidneys. Moreover, a slow restoration of normal pH values was observed three weeks after the glycerol injection. Conclusions pH appears to be a good parameter to assess the early detection of kidney injury as well as it acts as a reporter of the recovery toward the physiologic functionality
Heterogeneous enhancement pattern in DCE-MRI reveals the morphology of normal lymph nodes: an experimental study
Full text linkPurpose: To investigate the heterogeneous enhancement pattern in normal lymph nodes of healthy mice by different albumin-binding contrast agents. Methods: The enhancement of normal lymph nodes was assessed in mice by dynamic contrast-enhanced MRI (DCE-MRI) after the administration of two contrast agents characterized by different albumin-binding properties: gadopentetate dimeglumine (Gd-DTPA) and gadobenate dimeglumine (Gd-BOPTA). To take into account potential heterogeneities of the contrast uptake in the lymph nodes, k-means cluster analysis was performed on DCE-MRI data. Cluster spatial distribution was visually assessed. Statistical comparison among clusters and contrast agents was performed on semiquantitative parameters (AUC, wash-in rate, and wash-out rate) and on the relative size of the segmented clusters. Results: Cluster analysis of DCE-MRI data revealed at least two main clusters, localized in the outer portion and in the inner portion of each lymph node. With both contrast agents, AUC (p < 0.01) and wash-in (p < 0.05) rates were greater in the inner cluster, which also showed a steeper wash-out rate than the outer cluster (Gd-BOPTA, p < 0.01; Gd-DTPA, p=0.056). The size of the outer cluster was greater than that of the inner cluster by Gd-DTPA (p < 0.05) and Gd-BOPTA (p < 0.01). The enhancement pattern of Gd-DTPA was not significantly different from the enhancement pattern of Gd-BOPTA. Conclusion: DCE-MRI in normal lymph nodes shows a characteristic heterogeneous pattern, discriminating the periphery and the central portion of the lymph nodes. Such a pattern deserves to be investigated as a diagnostic marker for lymph node staging
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe 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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