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La anemia es una de las complicaciones más comunes de la enfermedad inflamatoria intestinal. La alta frecuencia de valores bajos de hemoglobina en estos enfermos provoca en muchas ocasiones una infravaloración por parte del médico de esta circunstancia, lo que se traduce en la falta de un tratamiento eficaz. Por otro lado, el carácter complejo de los mecanismos de producción de la anemia en la enfermedad inflamatoria intestinal con frecuencia plantea dudas acerca del tratamiento más adecuado. La identificación correcta de los pacientes con anemia así como la instauración del tratamiento más idóneo serán los dos pilares fundamentales para la mejoría de la calidad de vida de los enfermos. El uso correcto de los suplementos de hierro y las nuevas formulaciones de hierro parenteral, con o sin eritropoyetina asociada, han revolucionado nuestro abordaje de esta complicación evolutiva de la enfermedad inflamatoria intestinal Anemia is a most common complication of inflammatory bowel disease. A high frequency of low hemoglobin values in these patients often leads physicians to subestimate this condition, which translates into ineffective treatment. On the other hand, the complex nature of anemia-inducing mechanisms in inflammatory bowel disease frequently raises doubt about the most appropriate therapy. A correct identification of patients with anemia, and adequate therapy are the essential pillars for improved quality of life. The right use of iron supplementation, and novel parenteral iron formulations, either with or without associated erythropoietin, have revolutionized our approach of this complication in the course of inflammatory bowel disease

La impedancia esofágica multicanal constituye una de las más recientes herramientas diagnósticas aplicadas a la evaluación de la enfermedad por reflujo gastroesofágico. Esta técnica se basa en la monitorización continua de la conductividad eléctrica en un medio, en este caso el esófago, a través de electrodos situados en la longitud de una sonda, y en los cambios que un elemento como el bolo alimentario puede producir en dicha variable. De esta técnica se derivan nuevas perspectivas en la exploración de la función esofágica y de la enfermedad por reflujo gastroesofágico, hasta ahora sólo cuantificable de forma indirecta por las fluctuaciones generadas por los cambios en el pH del reflujo ácido. Presentamos el caso de una paciente con tos persistente evaluada con este procedimiento, en quien se demostró la presencia de reflujo gastroesofágico débilmente ácido que no pudo ser demostrado previamente con otras exploraciones, y de cómo la impedancia descartó la asociación entre este síntoma y el reflujo no ácido. Multichannel intraluminal impedance is a new technique for evaluating esophageal function and gastroesophageal reflux disease (GERD). This technique relies on the monitoring of electric conductivity in the esophagus though electrodes, and on changes developing in this variable as a result of bolus passage. The proximal distribution and duration of non-acid reflux events can now be quantified, and combined manometry defines the effectiveness of esophageal body function, until now only indirectly evaluated with pH changes. We discuss the case of a woman with persistent cough in whom intraesophageal multichannel impedance demostrates a minor acid reflux that could not be demonstrated with other diagnostic methods previously, and how this technique excludes any association between cough and non-acid reflux.

La anemia es una de las complicaciones más comunes de la enfermedad inflamatoria intestinal. La alta frecuencia de valores bajos de hemoglobina en estos enfermos provoca en muchas ocasiones una infravaloración por parte del médico de esta circunstancia, lo que se traduce en la falta de un tratamiento eficaz. Por otro lado, el carácter complejo de los mecanismos de producción de la anemia en la enfermedad inflamatoria intestinal con frecuencia plantea dudas acerca del tratamiento más adecuado. La identificación correcta de los pacientes con anemia así como la instauración del tratamiento más idóneo serán los dos pilares fundamentales para la mejoría de la calidad de vida de los enfermos. El uso correcto de los suplementos de hierro y las nuevas formulaciones de hierro parenteral, con o sin eritropoyetina asociada, han revolucionado nuestro abordaje de esta complicación evolutiva de la enfermedad inflamatoria intestinal

Ce travail de thèse consiste à développer un modèle hydrologique spécifique aux bassins versants urbains capable de représenter de manière distribuée les processus physiques importants en milieu urbain et pourtant souvent négligés dans les modèles classiques, tels que l'évapotranspiration, l'infiltration directe d'eau du sol dans les réseaux ou l'évolution temporelle du niveau de saturation dans le sol. Le modèle URBS (Urban Runoff Branching Structure) est basé sur les informations disponibles dans les Banques de données urbaines, à l'échelle de l'Elément Hydrologique basé sur la parcelle cadastrale. L'Etude de sensibilité du modèle aux paramètres d'entrée montre l'influence d'un paramètre d'infiltration directe dans les réseaux et de la conductivité hydraulique à saturation du sol. Le modèle est appliqué à plusieurs bassins urbains afin de tester la pertinence des résultats. Les bassins versants de Rezé (4.6 ha) et des Gohards (178 ha) permettent d'évaluer les débits simulés à l'exutoire ainsi que les niveaux de saturation simulés par comparaison aux mesures correspondantes. Les possbilités d'application du modèle URBS sont nombreuses, notamment pour contribuer au développement d'un outil d'aide à l'aménagement des bassins urbanis, par exemple en représentant l'influence des techniques alternatives en assainissement pluvial à l'échelle des bassins versants. Le modèle URBS permettant de prendre en considération la distribution spatiale des précipitations, des images radar à résolution spatiale très fine (250 m) sont exploitées pour illustrer l'influence de la variabilité spatiale des précipitations sur la réponse hydrologique de bassins versants urbains réels et fictifs. Une approche théorique permet de quantifier la variabilité des hydrogrammes en fonction d'une caractérisation statistique de la variabilité des précipitations. This Phd work presents the URBS (Urban Runoff Branching Structure) model especially dedicated to simulate urban catchments hydrology. The model accounts for physical processes that are usually neglected in urban hydrological models, such as evapotranspiration, direct infiltration into drainage sewers or temporal evolution of saturated soil level. URBS model is based on available information of urban databanks, and its basic modeling unit is the Hydrological Element, which main component is the cadastral parcel.The sensitivity of the URBS model to its major input parameters illustrated the influence of a parameter of direct infiltration into sewers and of the soil hydraulic conductivity on the catchment hydrology. A first validation was carried out over several urban catchments in order to evaluate the model relevance. Simulation results, including outlet runoff and soil saturation level were compared with corresponding measured data on Reze (4.6 ha) and Gohards (178 ha) catchments. This model could contribute to create a development-aid tool for urban catchments, and a possible application of this is presented with the representation of innovative stormwater technologies at catchment scale.The model allowing to take into account spatial distribution of precipitation, meteorological radar data with a small spatial resolution (250m) were used to illustrate the influence of rainfall spatial distribution on the hydrological response of urban catchments on both real and fictitious catchments. A theoretical approach allows quantifying hydrograms variability depending on statistical characterization of rainfall variability.

Multichannel intraluminal impedance is a new technique for evaluating esophageal function and gastroesophageal reflux disease (GERD). This technique relies on the monitoring of electric conductivity in the esophagus though electrodes, and on changes developing in this variable as a result of bolus passage. The proximal distribution and duration of non-acid reflux events can now be quantified, and combined manometry defines the effectiveness of esophageal body function, until now only indirectly evaluated with pH changes. We discuss the case of a woman with persistent cough in whom intraesophageal multichannel impedance demostrates a minor acid reflux that could not be demonstrated with other diagnostic methods previously, and how this technique excludes any association between cough and non-acid reflux.

Acute Myeloid Leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. Adoptive cell therapy by chimeric antigen receptor (CAR)-engineered T cells demonstrated a high therapeutic potential, but further development is required to ensure a safe and durable disease remission in AML, especially in elderly patients. To date, translation of CAR T cell therapy in AML is limited by the absence of an ideal tumor-specific antigen. CD123 and CD33 are the two most widely overexpressed LSCs biomarkers but their shared expression with endothelial and hematopoietic stem and progenitor cells (HSPCs) increases the risk of undesired vascular and hematologic toxicities. To counteract this issue, we established a balanced Dual CAR strategy aimed at reducing off-target toxicities while retaining full functionality against AML. Cytokine-Induced Killer (CIK) cells, co-expressing a first-generation low affinity anti-CD123 IL3-zetakine and an anti-CD33 as costimulatory receptor (CCR) without activation signaling domains, demonstrated a powerful antitumor efficacy against AML targets without any relevant toxicity on HSPCs and endothelial cells. The proposed optimized Dual CAR CIK strategy could offer the opportunity to unleash the potential of specifically target CD123+/CD33+ leukemic cells while minimizing toxicity against healthy cells.

Herein, we explored the impact of the lysosome dysfunction during the progression of Amyotrophic Lateral Sclerosis type-1 (ALS1). We conducted the study in non-neural cells, primary fibroblasts (rFFFs), and bone marrow-mesenchymal stem cells (rBM-MSCs), isolated from the animal model ratG93A for ALS1 at two stages of the disease: Pre-symptomatic-stage (ALS1-PreS) and Terminal-stage (ALS1-EndS). We documented the storage of human mutant Superoxide Dismutase 1, SOD1G93A (SOD1*) in the lysosomes of ALS1-rFFFs and ALS1-rBM-MSCs and demonstrated the hallmarks of the disease in non-neural cells as in ratG93A-ALS1-tissues. We showed that the SOD1* storage is associated with the altered glycohydrolases and proteases levels in tissues and both cell types from ALS1-PreS to ALS1-EndS. Only in ALS1-rFFFs, the lysosomes lost homeostasis, enlarge drastically, and contribute to the cell metabolic damage. Contrariwise, in ALS1-rBM-MSCs, we found a negligible metabolic dysfunction, which makes these cells’ status similar to WT. We addressed this phenomenon to a safety mechanism perhaps associated with an enhanced lysosomal autophagic activity in ALS1-rBM-MSCs compared to ALS1-rFFFs, in which the lysosomal level of LC3-II/LC3I was comparable to that of WT-rFFFs. We suggested that the autophagic machinery could balance the storage of SOD1* aggregates and the lysosomal enzyme dysfunction even in ALS1-EndS-stem cells.

Herein, we present poly(butylene 1,4-cyclohexanedicarboxylate) (PBCE) films characterized by an unpatterned microstructure and a specific hydrophobicity, capable of boosting a drastic cytoskeleton architecture remodeling, culminating with the neuronal-like differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs). We have used two different filming procedures to prepare the films, solvent casting (PBCE) and compression-moulding (PBCE*). PBCE film had a rough and porous surface with spherulite-like aggregations (&Oslash, = 10&ndash, 20 &mu, m) and was characterized by a water contact angle = 100&deg, PBCE* showed a smooth and continuous surface without voids and visible spherulite-like aggregations and was more hydrophobic (WCA = 110&deg, ). Both surface characteristics were modulated through the copolymerization of different amounts of ether-oxygen-containing co-units into PBCE chemical structure. We showed that only the surface characteristics of PBCE-solvent-casted films steered hBM-MSCs toward a neuronal-like differentiation. hBM-MSCs lost their canonical mesenchymal morphology, acquired a neuronal polarized shape with a long cell protrusion (&ge, 150 &mu, m), expressed neuron-specific class III &beta, tubulin and microtubule-associated protein 2 neuronal markers, while nestin, a marker of uncommitted stem cells, was drastically silenced. These events were observed as early as 2-days after cell seeding. Of note, the phenomenon was totally absent on PBCE* film, as hBM-MSCs maintained the mesenchymal shape and behavior and did not express neuronal/glial markers.

In the present review paper, our main results on nanocomposites based on biodegradable polymers (on a time scale from 2010 to 2018) are reported. We mainly focused our attention on commercial biodegradable polymers, which we mixed with different nanofillers and/or additives with the final aim of developing new materials with tunable specific properties. A wide list of nanofillers have been considered according to their shape, properties, and functionalization routes, and the results have been discussed looking at their roles on the basis of different adopted processing routes (solvent-based or melt-mixing processes). Two main application fields of nanocomposite based on biodegradable polymers have been considered: the specific interaction with stem cells in the regenerative medicine applications or as antimicrobial materials and the active role of selected nanofillers in food packaging applications have been critically revised, with the main aim of providing an overview of the authors’ contribution to the state of the art in the field of biodegradable polymeric nanocomposites.

Globoid cell leukodystrophy (GLD) is an inherited lysosomal storage disease caused by β-galactocerebrosidase (GALC) deficiency. Gene therapy (GT) should provide rapid, extensive and lifetime GALC supply in central nervous system (CNS) tissues to prevent or halt irreversible neurologic progression. Here we used a lentiviral vector (LV) to transfer a functional GALC gene in the brain of Twitcher mice, a severe GLD model. A single injection of LV.GALC in the external capsule of Twitcher neonates resulted in robust transduction of neural cells with minimal and transient activation of inflammatory and immune response. Importantly, we documented a proficient transduction of proliferating and post-mitotic oligodendroglia, a relevant target cell type in GLD. GALC activity (30–50% of physiological levels) was restored in the whole CNS of treated mice as early as 8 days post-injection. The early and stable enzymatic supply ensured partial clearance of storage and reduction of psychosine levels, translating in amelioration of histopathology and enhanced lifespan. At 6 months post-injection in non-affected mice, LV genome persisted exclusively in the injected region, where transduced cells overexpressed GALC. Integration site analysis in transduced brain tissues showed no aberrant clonal expansion and preferential targeting of neural-specific genes. This study establishes neonatal LV-mediated intracerebral GT as a rapid, effective and safe therapeutic intervention to correct CNS pathology in GLD and provides a strong rationale for its application in this and similar leukodystrophies, alone or in combination with therapies targeting the somatic pathology, with the final aim of providing an effective and timely treatment of these global disorders.

Globoid cell leukodystrophy (GLD) is a demyelinating lysosomal storage disease due to the deficiency of the galactocerebrosidase (GALC) enzyme. The favorable outcome of hematopoietic stem and progenitor cell (HSPC)-based approaches in GLD and other similar diseases suggests HSPC gene therapy as a promising therapeutic option for patients. The path to clinical development of this strategy was hampered by a selective toxicity of the overexpressed GALC in the HSPC compartment. Here, we presented the optimization of a lentiviral vector (LV) in which miR-126 regulation was coupled to codon optimization of the human GALC cDNA to obtain a selective and enhanced enzymatic activity only upon transduced HSPCs differentiation. The safety of human GALC overexpression driven by this LV was extensively demonstrated in vitro and in vivo on human HSPCs from healthy donors. No perturbation in the content of proapoptotic sphingolipids, gene expression profile, and capability of engraftment and mutlilineage differentiation in chimeric mice was observed. The therapeutic potential of this LV was then assessed in a severe GLD murine model that benefited from transplantation of corrected HSPCs with longer survival and ameliorated phenotype as compared to untreated siblings. This construct has thus been selected as a candidate for clinical translation.