Glia envolvente olfatoria modificada genéticamente mediante introducción de telomerasa

Referencia OEPM: P200100909.-- Fecha de solicitud: 19/04/2001.-- Titular: Consejo Superior de Investigaciones Científicas (CSIC).La presente invención consiste en la utilización de la glía envolvente olfatoria modificada mediante introducción de telomerasa o de cualquier molécula o moléculas que ésta produce, bien sea sola o en combinación con otras estrategias reparadoras, para tratar lesiones del sistema nervioso de mamíferos, incluidos los primates.Peer reviewe

Contribution of cardio-vascular risk factors to depressive status in the PREDIMED-PLUS Trial. A cross-sectional and a 2-year longitudinal study

Background Cardio-vascular disease and depression are thought to be closely related, due to shared risk factors. The aim of the study was to determine the association between cardio-vascular risk (CVR) factors and depressive status in a population (55-75 years) with metabolic syndrome (MetS) from the PREDIMED-Plus trial. Methods and findings Participants were classified into three groups of CVR according to the Framingham-based REGICOR function: (1) low (LR), (2) medium (MR) or (3) high/very high (HR). The Beck Depression Inventory-II (BDI-II) was used to assess depressive symptoms at baseline and after 2 years. The association between CVR and depressive status at baseline (n = 6545), and their changes after 2 years (n = 4566) were evaluated through multivariable regression models (logistic and linear models). HR women showed higher odds of depressive status than LR [OR (95% CI) = 1.78 (1.26, 2.50)]. MR and HR participants with total cholesterol <160 mg/mL showed higher odds of depression than LR [OR (95% CI) = 1.77 (1.13, 2.77) and 2.83 (1.25, 6.42) respectively)] but those with total cholesterol ¿280 mg/mL showed lower odds of depression than LR [OR (95% CI) = 0.26 (0.07, 0.98) and 0.23 (0.05, 0.95), respectively]. All participants decreased their BDI-II score after 2 years, being the decrease smaller in MR and HR diabetic compared to LR [adjusted mean±SE = -0.52±0.20, -0.41 ±0.27 and -1.25±0.31 respectively). MR and HR participants with total cholesterol between 240-279 mg/mL showed greater decreases in the BDI-II score compared to LR (adjusted mean±SE = -0.83±0.37, -0.77±0.64 and 0.97±0.52 respectively). Conclusions Improving cardiovascular health could prevent the onset of depression in the elderly. Diabetes and total cholesterol in individuals at high CVR, may play a specific role in the precise response.The PREDIMED-Plus trial was supported by the European Research Council through a grant to MAM (Advanced Research Grant 2013-2018; 340918). The project was also supported by the official funding agency for biomedical research of the Spanish Government (ISCIII) through the Fondo de Investigación para la Salud (FIS), which is co-funded by the European Regional Development Fund (four coordinated FIS projects), who awarded grants to JS and JV (PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732 and PI17/00926). The International Nut&Dried Fruit Council-FESNAD also provided funding through a grant to MAM (201302), and Recercaixa also awarded a grant to JS (2013ACUP00194). The Department of Health, Generalitat de Cataluña by the calls 'Acció instrumental de programes de recerca orientats en lámbit de la recercaila innovació en salut' and 'Pla estrategic de recerca i innovació en salut (PERIS),' also awarded a grant to FF (SLT006/17/00246). This research was also partially funded by: Consejería de Salud de la Junta de Andalucía (PI0458/2013, PS0358/2016, PI0137/2018); Generalitat Valenciana (PROMETEO/2017/017); SEMERGEN, CIBEROBN, FEDER and ISCIII (CB06/03); EU-H2020 Grants (Eat2beNICE/h2020-sfs-2016-2, ref.728018; PRIME/h2020-SC1-BHC-2018-2020, ref: 847879)

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

GLIA envolvente: caracterización y papel como promotora de la regeneración en el sistema nervioso central

Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Morfología. Fecha de lectura: 16 de Diciembre de 199

Regeneration into the spinal cord of transected dorsal root axons is promoted by ensheathing glia transplants

The permissivity of adult olfactory bulb to the ingrowth of olfactory axons could be due to the unique properties of ensheathing glia. To test whether these glial cells could be used to promote axonal regeneration in a spontaneously nonregenerating system, we transplanted suspensions of pure ensheathing cells into a rhizotomized spinal cord segment. Ensheathing cells were purified away from other cell types by immunoaffinity, using anti-p75 nerve growth factor receptor. After laminectomy at the lower thoracic level, the spinal cord was exposed and one dorsal root (T10) was completely transected at the cord entry point. The root stump was microsurgically anastomosed mosed to the cord and a suspension of ensheathing cells was transplanted in the spinal cord at the dorsal root entry zone. Three weeks after transplantation, numerous regenerating dorsal root axons were observed reentering the spinal cord. Ingrowth of dorsal root axons was observed using DiI and antibodies against calcitonin gene-related peptide and growth-associated protein. Primary sensory afferents invaded laminae 1, 2, and 3, grew through laminae 4 and 5, and reached the dorsal grey commissure and lamina 4 of the contralateral side. We did not observe regenerating axons within the ipsilateral ventral horn and dorsal column. Transplanted ensheathing cells reached the same laminae as axons. Neither ensheathing cells nor regenerating axons invaded those laminae they did not inervate under normal circumstances. In conclusion, the regeneration of injured dorsal root axons into the adult spinal cord was possible after ensheathing glia transplantation. The use of ensheathing cells as stimulators of axonal growth might be generalized to other central nervous system injuries.Peer Reviewe

Glial cells from adult rat olfactory bulb: Immunocytochemical properties of pure cultures of ensheathing cells

Three morphologically and immunohistochemically distinct types of cell were present in primary cultures of adult rat olfactory nerve and glomerular layers of the olfactory bulb. One cell type was multipolar and stained positively for glial fibrillary acidic protein; a second type had fried egg-like morphology and stained with antibodies to epitope ED1; the third cell type had fusiform morphology, reacted with antibodies to vimentin and laminin and was glial fibrillary acidic protein- and ED1-negative. Trypsinization of these primary cultures (3 min, 37°C), detached multipolar and fusiform cells only. When detached cells were set up in secondary culture on a glass substrate, fusiform cells did not attach, resulting in a pure culture of multipolar cells. Multipolar cells were glial fibrillary acidic protein- and myelin basic protein-positive and had the properties of so-called ensheathing cells or Blanes' glia. Immunoreactivity with anti-nerve growth factor receptor and anti-fibronectin alllowed us to identify four distinct populations of multipolar ensheathing cells. One population was nerve growth factor receptor-positive, fibronectin-negative. A second was nerve growth factor receptor-negative and fibronectin-positive. A third was positive for both markers and the remaining cells did not stain for either of them. The morphological and immunological characteristics of cultured cells from olfactory nerve and glomerular layers were similar to those of Schwann cells and the similarities could account for the permissivity to axonal growth of the olfactory bulb.Peer Reviewe

Chronic spinal injury repair by adult OEG

42 p., figuras, apéndice, bibliografíaOlfactory Bulb Ensheathing Glia (OB-OEG) promote spinal cord injury (SCI) repair in rats after transplantation at acute or subacute stages (up to 45 days). However, the most realistic clinical scenario is the chronic, in which no more cellular and molecular changes take place at the injury, and this occurs beyond the third month in rodents. Whether adult OB-OEG grafts promote repair of severe chronic SCI has not been previously addressed. Rats with complete SCI that were transplanted 4 months after injury exhibited a progressive improvement in motor function and axonal regeneration from different brainstem nuclei across and beyond the SCI site. A positive correlation between motor outcome and axonal regeneration suggested a role for brainstem neurons in the recovery. Functional and histological outcomes did not differ after transplantation at subacute or chronic stages. Thus, autologous transplantation is a feasible approach as there is a time-frame for patient stabilization and OEG preparation; moreover, the healing effects of OB-OEG on established injuries may offer new therapeutic opportunities for chronic SCI patients.This work was supported by the Ministry of Health (grant 01/1134), Ministry of Education and Science (SAF2004-04773), Fundación Investigación en Regeneración del Sistema Nervioso and the National Institutes of Health (Grant R01NS054159-01, subaward 0845 G GD202).Peer reviewe

Repair of central nervous system lesions by transplantation of olfactory ensheathing cells

Clinical conditions affecting the central nervous system (CNS) fall into two main categories – degenerative conditions in which nerve cells are lost (Alzheimer’s, Parkinson’s, Huntington’s disease, etc.), and traumatic insults which sever nerve fibers but leave their cell bodies and initial parts of the severed axons intact (spinal cord injury, cerebrovascular accidents, or tumors affecting fiber tracts). After injuries of this second type, the survival of the nerve cell bodies and the local sprouting at the severed ends of the proximal stumps of the axons raise the tantalizing possibility of one day learning how to induce these severed fibers to regenerate to their original targets and restore lost functions. This chapter gives an overview of current research into the strategy of transplantation of olfactory ensheathing cells into axotomizing injuries

In vitro enfolding of olfactory neurites by p75 NGF receptor positive ensheathing cells from adult rat olfactory bulb

Secondary cultures of adult rat olfactory bulb (OB) contained three different types of cells (i) process-bearing cells; (ii) macrophage-like cells and (iii) fusiform cells. The immunohistochemical properties of process-bearing cells closely corresponded to those described for ensheathing glia in vivo. The most distinctive feature of these cells was their immunoreactivity for low affinity nerve growth factor receptor (NGFR). Process-bearing cells also shared the ultrastructural properties of ensheathing glia in vivo, as well as the ability to ensheath olfactory axons. In contrast, macrophage-like cells had the immunostaining properties of microglia, and fusiform cells were likely capillary endothelial cells. Neurites outgrowing from olfactory epithelium explants, when co-cultured with adult OB cells, grew preferentially over NGFR positive cells. Olfactory neurites exhibited NGFR immunoreactivity and were enfolded by NGFR positive cells. After ensheathment, this immunoreactivity decreased from the neurite and disappeared from the glial membrane in contact with the neurite. However, NGFR immunoreactivity was maintained in the portion of the glial membrane not involved in ensheathing. In summary, ensheathing cells in vitro retained both the ultrastructure shown in vivo and the ability to ensheath olfactory neurites. The Schwann cell-like properties of ensheathing glia, could partially explain the permissibility of adult OB to axonal growth.Peer Reviewe