Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells

BACKGROUND: In obstructive congenital hydrocephalus, cerebrospinal fluid accumulation is associated with high intracranial pressure and the presence of periventricular edema, ischemia/hypoxia, damage of the white matter, and glial reactions in the neocortex. The viability and short time effects of a therapy based on bone marrow-derived mesenchymal stem cells (BM-MSC) have been evaluated in such pathological conditions in the hyh mouse model. METHODS: BM-MSC obtained from mice expressing fluorescent mRFP1 protein were injected into the lateral ventricle of hydrocephalic hyh mice at the moment they present a very severe form of the disease. The effect of transplantation in the neocortex was compared with hydrocephalic hyh mice injected with the vehicle and non-hydrocephalic littermates. Neural cell populations and the possibility of transdifferentiation were analyzed. The possibility of a tissue recovering was investigated using 1H High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, thus allowing the detection of metabolites/osmolytes related with hydrocephalus severity and outcome in the neocortex. An in vitro assay to simulate the periventricular astrocyte reaction conditions was performed using BM-MSC under high TNFα level condition. The secretome in the culture medium was analyzed in this assay. RESULTS: Four days after transplantation, BM-MSC were found undifferentiated and scattered into the astrocyte reaction present in the damaged neocortex white matter. Tissue rejection to the integrated BM-MSC was not detected 4 days after transplantation. Hyh mice transplanted with BM-MSC showed a reduction in the apoptosis in the periventricular neocortex walls, suggesting a neuroprotector effect of the BM-MSC in these conditions. A decrease in the levels of metabolites/osmolytes in the neocortex, such as taurine and neuroexcytotoxic glutamate, also indicated a tissue recovering. Under high TNFα level condition in vitro, BM-MSC showed an upregulation of cytokine and protein secretion that may explain homing, immunomodulation, and vascular permeability, and therefore the tissue recovering. CONCLUSIONS: BM-MSC treatment in severe congenital hydrocephalus is viable and leads to the recovery of the severe neurodegenerative conditions in the neocortex. NMR spectroscopy allows to follow-up the effects of stem cell therapy in hydrocephalus.España Instituto Carlos III , PI15/00619 (to AJJ), PI19/00778 (to AJJ and PPG), PI15/00796, and PI18/01557España Ministerio de Educación, Cultura y Deporte FPU13/02906España, Ministerio de Economía y Competitividad RYC-2014-16980España, FEDER Andalucía y Universidad de Málaga UMA18-FEDERJA-27

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Evaluation of biocompatibility and biodegradability of a new vitreous silica-based material

Motivation: Biomaterials have an importal role in tissue regeneration so that they must perform some features. Biomaterials have to be biocompatible with the body, that is, accept it without causing reactions of rejection or toxicity, as inflammatory responses or blood clotting; and also help the cells around him to continue performing their vital processes. Furthermore, it has to be bioresorbable, it mean, it must have the capacity to degrade partially or totally in a suitable period of time so that the organism can to metabolize it and replace it with new tissue.This work's main objetive is to evaluate a new silica-based vitreous material (BCG) in vivo by testing in an animal model. For this, the biocompatibility and biodegradability of the material will be studied.Methods: The material was implanted subcutaneously in adult rats of the Wistar strain. A magnetic resonance imaging (MRI) device was used for the weekly monitoring of the implants in a non-invasive way. After 28 days, the animals were sacrificed, and it was studied by image acquisition by computerized axial tomography (CAT). The implants were isolated for further histological processing.The images of MRI and CAT were subjected to image analysis to determine the volume of the implants in each sample time, and from this point, their degradation rate in vivo. The implants extracted from the animals were included in resin and histological sections were obtained. Different stains were performed such as hematoxylin-eosin to observe the general state of the tissue, picrosirio to observe the deposition of collagen in the implants, Goldner's trichrome to differentiate several tissues, and histochemistry of lectins to observe blood vessels.Results and conclusions: The material does not produce fibrous cyst around the implanted tissue, and also does not show signs of chronic inflammatory response. The tissue of the animal has been able to colonize the material, producing blood irrigation and without causing acute alterations in the area of the implant. These results indicate that it is a biocompatible material that could be used for tissue regeneration. In addition, if it is a bioresorbable material, it will show a decrease in its volume, due to the degradation in the successive weeks of implementation

Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells

Background: In obstructive congenital hydrocephalus, cerebrospinal fluid accumulation is associated with high intracranial pressure and the presence of periventricular edema, ischemia/hypoxia, damage of the white matter, and glial reactions in the neocortex. The viability and short time effects of a therapy based on bone marrow-derived mesenchymal stem cells (BM-MSC) have been evaluated in such pathological conditions in the hyh mouse model. Methods: BM-MSC obtained from mice expressing fluorescent mRFP1 protein were injected into the lateral ventricle of hydrocephalic hyh mice at the moment they present a very severe form of the disease. The effect of transplantation in the neocortex was compared with hydrocephalic hyh mice injected with the vehicle and non-hydrocephalic littermates. Neural cell populations and the possibility of transdifferentiation were analyzed. The possibility of a tissue recovering was investigated using 1H High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, thus allowing the detection of metabolites/osmolytes related with hydrocephalus severity and outcome in the neocortex. An in vitro assay to simulate the periventricular astrocyte reaction conditions was performed using BM-MSC under high TNFα level condition. The secretome in the culture medium was analyzed in this assay. Results: Four days after transplantation, BM-MSC were found undifferentiated and scattered into the astrocyte reaction present in the damaged neocortex white matter. Tissue rejection to the integrated BM-MSC was not detected 4 days after transplantation. Hyh mice transplanted with BM-MSC showed a reduction in the apoptosis in the periventricular neocortex walls, suggesting a neuroprotector effect of the BM-MSC in these conditions. A decrease in the levels of metabolites/osmolytes in the neocortex, such as taurine and neuroexcytotoxic glutamate, also indicated a tissue recovering. Under high TNFα level condition in vitro, BM-MSC showed an upregulation of cytokine and protein secretion that may explain homing, immunomodulation, and vascular permeability, and therefore the tissue recovering. Conclusions: BM-MSC treatment in severe congenital hydrocephalus is viable and leads to the recovery of the severe neurodegenerative conditions in the neocortex. NMR spectroscopy allows to follow-up the effects of stem cell therapy in hydrocephalus.The present work was supported by Grants PI15/00619 (to AJJ), PI19/00778 (to AJJ and PPG), PI15/00796, and PI18/01557 (to AG) from the Instituto de Salud Carlos III, Spain, co-financed by FEDER funds from the European Union from the Instituto de Salud Carlos III, Spain, PU13/02906 to MGB from the Ministerio de Educación, Cultura y Deporte, Spain; and RYC-2014-16980 to PPG from the Ministerio de Economía y competitividad, Spain. Ayudas para publicación en abierto del plan propio (to AJJ) from Universidad de Málaga. UMA18-FEDERJA-277 (to PPG) from Plan Operativo FEDER Andalucía 2014-2020 and Universidad de Málaga. Proyectos dirigidos por jóvenes investigadores (to PPG) from Universidad de Málaga.Ye

Memorias VIII Coloquio Perspectivas Metodológicas y Pedagógicas de la Investigación en Lengua Materna

La investigación como campo de actuación profesional requiere que las dimensiones del ser y del hacer del profesor se expliciten mediante actitudes y aptitudes desde las cuales se incida en procesos de innovación y transformación educativa y cultural, coherentes con el contexto histórico-social del momento. "Perspectivas de la Investigación en Pedagogía de la Lengua Materna y la Literatura" presenta el trabajo de discusión académica desarrollado en el VIII Coloquio en Pedagogía de la Lengua Materna, a propósito de los estatutos metódicos, teóricos y pedagógicos involucrados en el devenir de las investigaciones sobre la enseñanza -aprendizaje de la lengua materna y de la literatura, como también sobre el proceso de formación del docente - investigador en este campo.Research as a field of professional action requires that the dimensions of the being and of the teacher be made explicit through attitudes and skills from which the processes of innovation and educational and cultural transformation are based, coherent with the historical-social context of the moment. "Perspectives of Research in Pedagogy of the Mother Tongue and Literature" presents the academic discussion work developed in the VIII Colloquium in Pedagogy of the Mother Tongue, with regard to the methodical, theoretical and pedagogical statutes involved in the evolution of research on teaching - learning the mother tongue and literature, as well as the process of teacher training - researcher in this field.Bogotá-Colombi

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P <.001). Overall motor and cognitive performance (P <.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P <.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P <.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P <.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients