Clinical and molecular features and therapeutic perspectives of spinal muscular atrophy with respiratory distress type 1

Spinal muscular atrophy with respiratory distress (SMARD1) is an autosomal recessive neuromuscular disease caused by mutations in the IGHMBP2 gene, encoding the immunoglobulin μ-binding protein 2, leading to motor neuron degeneration. It is a rare and fatal disease with an early onset in infancy in the majority of the cases. The main clinical features are muscular atrophy and diaphragmatic palsy, which requires prompt and permanent supportive ventilation. The human disease is recapitulated in the neuromuscular degeneration (nmd) mouse. No effective treatment is available yet, but novel therapeutical approaches tested on the nmd mouse, such as the use of neurotrophic factors and stem cell therapy, have shown positive effects. Gene therapy demonstrated effectiveness in SMA, being now at the stage of clinical trial in patients and therefore representing a possible treatment for SMARD1 as well. The significant advancement in understanding of both SMARD1 clinical spectrum and molecular mechanisms makes ground for a rapid translation of pre-clinical therapeutic strategies in humans

Functionalizing Ti-Surfaces through the EPD of Hydroxyapatite/NanoY₂O₃

Ceramic materials for skeletal repair and reconstruction are expanding to a number of different applications. Present research is addressing new compositions and performances to promote osseo-integration through metal coatings. Nanotechnology plays a key role in this research because nanostructures can be introduced into implants to functionalize them and/or to enhance their properties, such as the thermal or mechanical response. In this work, the insertion of Y₂O₃ nanoparticles into a hydroxyapatite (HA) coating of Ti using colloidal processing technology was developed. The suspensions of HA and Y₂O₃ nanoparticles were formulated with a focus on zeta potential, particle size distribution, and viscosity for the codeposition of both phases by electrophoresis. The microstructure of the nanocomposite coating was optimized by adjusting the main parameters of the electrophoretic deposition process. A threshold value of the applied electric field for the composite shaping was identified. The results demonstrate that the Y₂O₃ nanoparticles are homogeneously distributed in the coating and decrease in concentration as the distance from the substrate increases. As a consequence of the presence of the Y₂O₃, delays in the HA thermal decomposition and the improvement of metal–ceramic joining were observed.This work has been supported by the Spanish Ministry of Economy and Competitiveness (MINECO) under contracts MAT2009 14448 C02 01, MAT2012 38650 C02 02, and IPT 310000 2010 12

Immunohistochemical expression of the glucose transporters Glut-1 and Glut-3 in human malignant melanomas and benign melanocytic lesions

<p>Abstract</p> <p>Background</p> <p>Reported data indicate that cancer cells have increased rates of glucose metabolism, as determined by 18FDG-PET imaging in patients with malignancies. The results of many studies have demonstrated that the expression of glucose transporters, especially Glut-1, is increased in a variety of malignancies. This study was undertaken to assess the differential expression of Glut-1 and Glut-3 by benign and malignant melanocytic lesions.</p> <p>Methods</p> <p>Immunohistochemical staining for Glut-1 and Glut-3 was performed on paraffin-embedded tissue sections prepared from melanocytic nevi (12 cases), Spitz nevi (12 cases) and primary cutaneous malignant melanomas (20 cases).</p> <p>Results</p> <p>We observed immunoreactivity for Glut-1 in all melanocytic nevi, 9 of the 12 Spitz nevi and in 9 of the 20 malignant melanomas, whereas Glut-3 was expressed in all the melanocytic lesions, both benign and malignant.</p> <p>Conclusion</p> <p>These findings indicate that the glucose transporters Glut-1 and Glut-3 play a role in the glucose metabolism of melanocytic cells. Glut-1 was present in the majority of benign nevi, whereas its expression was downregulated in 55% of malignant melanomas. Our results suggest that glucose transporter Glut-1 expression can significantly discriminate between human malignant melanoma and benign melanocytic nevi, and support the idea that additional mechanisms other than Glut-1 may contribute to glucose uptake in melanomas.</p

Very Early Onset-IBD: evidence for the need of a multidisciplinary approach

Very early onset inflammatory bowel disease (VEO-IBD) represents approximately 25% of cases of IBD-like colitis occurring during childhood and, by definition, it is characterized by an onset prior to 6 years of age. This subgroup of patients presents significant differences from IBD occurring in older children and in adults, including a more severe clinical course, a reduced responsiveness to conventional IBD therapy, and a greater proportion of cases featuring an underlying monogenic disorder. Histological findings from gastro-intestinal (GI) biopsies are characterized by an IBD-like, apoptotic or enterocolitis-like pattern, complicating the differential diagnosis with other pediatric diseases involving GI tract. Moreover, individuals with monogenic disorders may develop significant comorbidities, such as primary immunodeficiency (PID), impacting treatment options. Without an appropriate diagnosis, the clinical course of VEO-IBD has greater potential for escalated treatment regimens involving extensive surgery, more intensive medical therapies and, even more important, inadequate recognition of underlying monogenic defect that may lead to inappropriate (sometimes fatal) therapy. For these reasons, an adequate context leading to an appropriate diagnosis is imperative, calling for a close collaboration between pediatricians, pathologists, geneticists, and immunologists

Positron annihilation study of defect distribution in 8YSZ nanostructure

The impact of the interfacial contribution on overall properties increases with decreasing grain size of polycrystalline materials. It is well known that distribution and size of cluster defects are rather different in bulk than grain boundaries. In light of "bottom-up" approaches, a study at the atomic level determining the distribution of crystallographic defects could clarify their contribution to the macroscopic properties, and then differentiate materials for outstanding or precise applications. In this work, Positron Annihilation Spectroscopy (PAS) is used to characterize the distribution of defects within 8 mol% Y₂O₃-stabilized zirconia (8YSZ) structures prepared by sintering through three different thermal treatments, i.e. a conventional thermal cycle in air and N₂/H₂ atmosphere, and a fast firing cycle in air, which lead to average grain sizes < 260 nm.The authors would like to acknowledge the financial support from the Spanish Government through the projects MAT2009-14448-C02-01 and IPT-310000-2010-12.Publicad

Role of intracellular and extracellular annexin A1 in migration and invasion of human pancreatic carcinoma cells

Background: Annexin A1 (ANXA1), a 37 kDa multifunctional protein, is over-expressed in tissues from patients of pancreatic carcinoma (PC) where the protein seems to be associated with malignant transformation and poor prognosis. Methods: The expression and localization of ANXA1 in MIA PaCa-2, PANC-1, BxPC-3 and CAPAN-2 cells were detected by Western Blotting and Immunofluorescence assay. Expression and activation of Formyl Peptide Receptors (FPRs) were shown through flow cytometry/PCR and FURA assay, respectively. To investigate the role of ANXA1 in PC cell migration and invasion, we performed in vitro wound-healing and matrigel invasion assays. Results: In all the analyzed PC cell lines, a huge expression and a variable localization of ANXA1 in sub-cellular compartments were observed. We confirmed the less aggressive phenotype of BxPC-3 and CAPAN-2 compared with PANC-1 and MIA PaCa-2 cells, through the evaluation of Epithelial-Mesenchymal Transition (EMT) markers. Then, we tested MIA PaCa-2 and PANC-1 cell migration and invasiveness rate which was inhibited by specific ANXA1 siRNAs. Both the cell lines expressed FPR-1 and -2. Ac2-26, an ANXA1 mimetic peptide, induced intracellular calcium release, consistent with FPR activation, and significantly increased cell migration/invasion rate. Interestingly, in MIA PaCa-2 cells we found a cleaved form of ANXA1 (33 kDa) that localizes at cellular membranes and is secreted outside the cells, as confirmed by MS analysis. The importance of the secreted form of ANXA1 in cellular motility was confirmed by the administration of ANXA1 blocking antibody that inhibited migration and invasion rate in MIA PaCa-2 but not in PANC-1 cells that lack the 33 kDa ANXA1 form and show a lower degree of invasiveness. Finally, the treatment of PANC-1 cells with MIA PaCa-2 supernatants significantly increased the migration rate of these cells. Conclusion: This study provides new insights on the role of ANXA1 protein in PC progression. Our findings suggest that ANXA1 protein could regulate metastasis by favouring cell migration/invasion intracellularly, as cytoskeleton remodelling factor, and extracellularly like FPR ligand

Effect of highly dispersed yttria addition on thermal stability of hydroxyapatite

The capability of the colloidal method to produce yttria (Y₂O₃) dispersed hydroxyapatite (HA) has been investigated as an alternative method to the conventional method of mechanical mixing and sintering for developing HA-based materials that could exhibit controllable and enhanced functional properties. A water based colloidal route to produce HA materials with highly dispersed Y₂O₃ has been applied, and the effect of 10 wt.% Y₂O₃ addition to HA investigated by thermal analysis, X-ray diffraction and Fourier transform infrared spectroscopy. These measurements evidence a remarkable effect of this Y₂O₃ addition on decomposition mechanisms of synthetic HA. Results show that incorporation of Y₂O₃ as dispersed second phase is beneficial because it hinders the decomposition mechanisms of HA into calcium phosphates. This retardation will allow the control of the sintering conditions for developing HA implants with improved properties. Besides, substitution of Ca⁻2+ with Y⁻3+ ions appears to promote the formation of OH- vacancies, which could improve the conductive properties of HA favorable to osseointegration.This work has been supported by the Ministry of Science and Innova tion of Spain (MICINN) under contracts MAT2009 14448 C02 01 and IPT 310000 2010 12, and Regional Government of Madrid through the ESTRUMAT CM program (MAT 1585).Publicad

Microstructural characterization of alumina-zirconia layered ceramics using positron annihilation spectroscopy

Positron annihilation spectroscopy (PAS), indentation, nanoindentation experiments and scanning electron microscopy (SEM) observations were performed on Al₂O₃-ZrO₂ laminates samples to assess the effect of residual stresses on their mechanical and microstructural properties. Layered samples were implemented by slip-casting, constituted by two thin Al₂O₃ external layers and an intermediate thick one, consisting of a mixture of Al₂O₃ and monoclinic ZrO₂ in the range 0-30 vol.%. In these systems residual tensile stresses fields were generated inside the external layers during cooling from the sintering temperature, by the expansion of the adjacent ZrO₂-containing layer. SEM observations showed the microstructural effects due to the level of tension related to the zirconia content. A correlation between the PAS parameters and the microstructural changes caused by the presence of residual stresses was found. Nanoindentation measurements were used to trace the sign and magnitude of the residual stress gradient across the interface between the layers.This work was supported by Spanish Government under Contract MAT2006-01038. The authors gratefully acknowledge the financial support from the Comunidad de Madrid and the Ministry of Education and Science of Spain, through the ESTRUMAT-CM (MAT/77) programs.Publicad