Histological and ultrastructural comparison of cauterization and thrombosis stroke models in immune-deficient mice

Background: Stroke models are essential tools in experimental stroke. Although several models of stroke have been developed in a variety of animals, with the development of transgenic mice there is the need to develop a reliable and reproducible stroke model in mice, which mimics as close as possible human stroke. Methods: BALB/Ca-RAG2-/-gc-/- mice were subjected to cauterization or thrombosis stroke model and sacrificed at different time points (48hr, 1wk, 2wk and 4wk) after stroke. Mice received BrdU to estimate activation of cell proliferation in the SVZ. Brains were processed for immunohistochemical and EM. Results: In both stroke models, after inflammation the same glial scar formation process and damage evolution takes place. After stroke, necrotic tissue is progressively removed, and healthy tissue is preserved from injury through the glial scar formation. Cauterization stroke model produced unspecific damage, was less efficient and the infarct was less homogeneous compared to thrombosis infarct. Finally, thrombosis stroke model produces activation of SVZ proliferation. Conclusions: Our results provide an exhaustive analysis of the histopathological changes (inflammation, necrosis, tissue remodeling, scarring...) that occur after stroke in the ischemic boundary zone, which are of key importance for the final stroke outcome. This analysis would allow evaluating how different therapies would affect wound and regeneration. Moreover, this stroke model in RAG 2-/- gC -/- allows cell transplant from different species, even human, to be analyzed

Therapeutic effects of hMAPC and hMSC transplantation after stroke in mice

Stroke represents an attractive target for stem cell therapy. Although different types of cells have been employed in animal models, a direct comparison between cell sources has not been performed. The aim of our study was to assess the effect of human multipotent adult progenitor cells (hMAPCs) and human mesenchymal stem cells (hMSCs) on endogenous neurogenesis, angiogenesis and inflammation following stroke. BALB/Ca-RAG 2(-/-) γC(-/-) mice subjected to FeCl(3) thrombosis mediated stroke were intracranially injected with 2 × 10(5) hMAPCs or hMSCs 2 days after stroke and followed for up to 28 days. We could not detect long-term engraftment of either cell population. However, in comparison with PBS-treated animals, hMSC and hMAPC grafted animals demonstrated significantly decreased loss of brain tissue. This was associated with increased angiogenesis, diminished inflammation and a glial-scar inhibitory effect. Moreover, enhanced proliferation of cells in the subventricular zone (SVZ) and survival of newly generated neuroblasts was observed. Interestingly, these neuroprotective effects were more pronounced in the group of animals treated with hMAPCs in comparison with hMSCs. Our results establish cell therapy with hMAPCs and hMSCs as a promising strategy for the treatment of strok

Therapeutic effects of hMAPC and hMSC transplantation after stroke in mice

Stroke represents an attractive target for stem cell therapy. Although different types of cells have been employed in animal models, a direct comparison between cell sources has not been performed. The aim of our study was to assess the effect of human multipotent adult progenitor cells (hMAPCs) and human mesenchymal stem cells (hMSCs) on endogenous neurogenesis, angiogenesis and inflammation following stroke. BALB/Ca-RAG 2(-/-) γC(-/-) mice subjected to FeCl(3) thrombosis mediated stroke were intracranially injected with 2 × 10(5) hMAPCs or hMSCs 2 days after stroke and followed for up to 28 days. We could not detect long-term engraftment of either cell population. However, in comparison with PBS-treated animals, hMSC and hMAPC grafted animals demonstrated significantly decreased loss of brain tissue. This was associated with increased angiogenesis, diminished inflammation and a glial-scar inhibitory effect. Moreover, enhanced proliferation of cells in the subventricular zone (SVZ) and survival of newly generated neuroblasts was observed. Interestingly, these neuroprotective effects were more pronounced in the group of animals treated with hMAPCs in comparison with hMSCs. Our results establish cell therapy with hMAPCs and hMSCs as a promising strategy for the treatment of strok

Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C : A prospective observational study

Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered 'suspected NP-C' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients. This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis

Measuring Urban Agglomeration: A Refoundation of the Mean City-Population Size Index

La relevancia de las economías de aglomeración tipo urbanización sobre múltiples variables y/o dinámicas económicas se encuentra ampliamente documentada en la literatura. Sin embargo, es difícil ofrecer una medida sintética del nivel de aglomeración urbana que alcanza un territorio. En este trabajo se propone un índice de aglomeración que cumple tres propiedades fundamentales: i) aumentar en función de la concentración de la población y cumplir el principio de transferencia de Pigou-Daltonii) aumentar con el tamaño absoluto del territorio donde se producen interacciones de la población, y iii) ser consistente en la agregación. Se desarrolla un índice de aglomeración en función del número de oportunidades de interacción por habitante en un área geográfica, que considera las interacciones de pares y la delineación espacial de mercados de trabajo locales (LLMA, por sus siglas en inglés). La medida es la esperanza matemática del tamaño del LLMA donde vive un individuo aleatorio y se asemeja a la propuesta de Arriaga (1970, 1975). Adicionalmente, el índice posee varias características importantes. No requiere un umbral de población arbitraria para separar urbano de no urbano. Se puede adaptar a los casos en los que un LLMA radica en parte fuera de la zona geográfica para la que se mide la aglomeración. Finalmente, se puede aproximar de forma adecuada cuando hay datos truncados o con una elevada agregación. Para evaluar el funcionamiento del índice, se examina su correlación con los coeficientes de localización de las actividades de servicios a empresas intensivos en conocimiento, de las provincias españolas. Las correlaciones son claramente más elevadas que las obtenidas con el índice clásico de urbanización o el índice de concentración de Hirschman-HerfindahlIn this paper, we put forth the view that the potential for urbanisation economies increases with interaction opportunities. On the basis of that premise, three properties are key to an agglomeration index, which should: (i) increase with the concentration of population and conform to the Pigou-Dalton transfer principle(ii) increase with the absolute size of constituent population interaction zonesand (iii) be consistent in aggregation. Confining our attention to pairwise interactions, and invoking the space-analytic foundations of local labour market area (LLMA) delineation, we develop an index of agglomeration based on the number of interaction opportunities per capita in a geographical area. This leads to Arriaga’s mean city-population size, which is the mathematical expectation of the size of the LLMA in which a randomly chosen individual lives. The index has other important properties. It does not require an arbitrary population threshold to separate urban from non-urban areas. It adapts readily to situations where an LLMA lies partly outside the geographical area for which agglomeration is measured. Finally, it can be satisfactorily approximated when data are truncated or aggregated into size classes. We apply the index to the Spanish NUTS III regions, and evaluate its performance by examining its correlation with the location quotients of several knowledge-intensive business services (KIBS) known to be highly sensitive to urbanisation economies. The Arriaga index correlations are clearly stronger than those of either the classical degree of urbanisation or the Hirshman-Herfindahl concentration inde