Activation of lysophosphatidic acid receptor type 1 (LPA1) contributes to pathophysiology of spinal cord injury

Altres ajuts: NIH/NS084398Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions that signals through six known G-protein-coupled receptors (LPA1-LPA6). A wide range of LPA effects have been identified in the CNS, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and development of neuropathic pain. However, little is known about the involvement of LPA in CNS pathologies. Herein, we demonstrate for the first time that LPA signaling via LPA1 contributes to secondary damage after spinal cord injury. LPA levels increase in the contused spinal cord parenchyma during the first 14 d. To model this potential contribution of LPA in the spinal cord, we injected LPA into the normal spinal cord, revealing that LPA induces microglia/macrophage activation and demyelination. Use of a selective LPA1 antagonist or mice lacking LPA1 linked receptor-mediated signaling to demyelination, which was in part mediated by microglia. Finally, we demonstrate that selective blockade of LPA1 after spinal cord injury results in reduced demyelination and improvement in locomotor recovery. Overall, these results support LPA-LPA1 signaling as a novel pathway that contributes to secondary damage after spinal cord contusion in mice and suggest that LPA1 antagonism might be useful for the treatment of acute spinal cord injur

Association of High Serum Levels of Growth Factors with Good Outcome in Ischemic Stroke : a Multicenter Study

Altres ajuts: This project was partially supported by grants from Xunta de Galicia (Consellería Educación: GRC2014/027 and IN607A2018/3), Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS PLUS (RD16/0019), and by the European Union FEDER program.The main objective of this research work was to study the association of serum levels of growth factors (GF) and SDF-1α with the functional outcome and reduction of lesion volume in ischemic stroke patients. In this multicenter study, 552 patients with non-lacunar stroke (male, 62.1%; mean age, 68.2 ± 11.4) were included within 24 h from symptom onset. The main outcome variable was good functional outcome (modified Rankin Scale [mRS] ≤ 2) at 12 months. Secondary outcome variable was infarct volume (in mL) after 6 ± 3 months. Serum levels of VEGF, Ang-1, G-CSF, BDNF, and SDF-1α were measured by ELISA at admission, 7 ± 1 days, at 3 ± 1 months, and 12 ± 3 months. Except for BDNF, all GF and SDF-1α serum levels showed a peak value at day 7 and remained elevated during the first 3 months (all p < 0.01). High serum levels at day 7 of VEGF (OR, 19.3), Ang-1 (OR, 14.7), G-CSF (OR, 9.6), and SDF-1α (OR, 28.5) were independently associated with good outcome at 12 months (all p < 0.0001). On the other hand, serum levels of VEGF (B, − 21.4), G-CSF (B, − 14.0), Ang-1 (B, − 13.3), and SDF-1α (B, − 44.6) measured at day 7 were independently associated with lesion volume at 6 months (p < 0.01). In summary, high serum levels of VEGF, Ang-1, G-CSF, and SDF-1α at day 7 and 3 months after ischemic stroke are associated with good functional outcome and smaller residual lesion at 1 year of follow-up

High within-host diversity found from direct genotyping on post-mortem tuberculosis specimens in a high-burden setting

Objectives: To characterize the clonal complexity in Mycobacterium tuberculosis (MTB) infections considering factors that help maximize the detection of coexisting strains/variants. Methods: Genotypic analysis by Mycobacterial Interspersed Repetitive-Unit-Variable-Number Tandem-Repeats (MIRU-VNTR) was performed directly on 70 biopsy specimens from two or more different tissues involving 28 tuberculosis cases diagnosed post-mortem in Mozambique, a country with a high tuberculosis burden. Results: Genotypic data from isolates collected from two or more tissues were obtained for 23 of the 28 cases (82.1%), allowing the analysis of within-patient diversity. MIRU-VNTR analysis revealed clonal diversity in ten cases (35.7%). Five cases showed allelic differences in three or more loci, suggesting mixed infection with two different strains. In half of the cases showing within-host diversity, one of the specimens associated with clonal heterogeneity was brain tissue. Conclusions: Direct MTB genotyping from post-mortem tissue samples revealed a frequent within-host Mycobacterium tuberculosis diversity, including mixed and polyclonal infections. Most of this diversity would have been overlooked if only standard analysis of respiratory specimens had been performed

Unha enxeñeira ou científica en cada cole

Póster presentado na V XORNADA UNIVERSITARIA GALEGA EN XÉNERO. TRANSFORMANDO DENDE A UNIVERSIDADE. Vigo, 7 Xullo 2017Nesta comunicación, presentamos o proxecto Unha enxeñeira ou científica en cada cole organizado pola Oficina de Igualdade de Xénero da Universidade de Santiago de Compostela (USC) en colaboración co Concello de Santiago de Compostela. Esta iniciativa pretende incentivar a presenza de rapazas en carreiras relacionadas coas disciplinas STEM (ciencia, enxeñería, tecnoloxía e matemáticas), mediante actividades didácticas nos centros educativos que rachen cos estereotipos sexistas da nosa sociedade. A actividade didáctica consistiu na realización de dezanove obradoiros, dirixidos a nenas e nenos de 5º ou 6º de primaria e realizados nos meses de setembro e outubro de 2016. Os obradoiros foron impartidos por profesoras ou investigadoras da USC e do Centro de Supercomputación de Galicia (CESGA) para crear referentes femininos e incentivar a presenza de rapazas no ámbito científico tecnolóxico. Ademais, estes obradoiros amosaron a relación da ciencia e da tecnoloxía coa nosa vida cotiá e serviron para achegar ao alumnado a estas disciplinas dun xeito lúdicoConcello de Santiago de Compostel

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Evaluación neurobiológica de electrodos regenerativos como interfase entre nervios lesionados y prótesis biónicas

El uso de neuroprótesis, desarrolladas para sustituir artificialmente o mimetizar funciones sensorimotoras en pacientes con déficits neurológicos, incluyen la utilización de interfases en el Sistema Nervioso Periférico a través de electrodos, los cuales permiten la estimulación neuromuscular y el registro de señales neurales. Los electrodos regenerativos estan diseñados con el fin de ser implantados entre los extremos seccionados de un nervio periférico creando asi una interfase regenerativa capaz de estimular y de registrar señales neurales. La aplicabilidad de estos electrodos depende del éxito de la regeneración axonal a través de las perforaciones del electrodo regenerativo, del posible daño nervioso debido a la carga mecánica impuesta por el electrodo o por fuerzas constrictivas dentro de las perforaciones, y de la biocompatibilidad de los componentes, especialmente en una implantación crónica. Los objetivos del presente trabajo han sido, en primer lugar, la evaluación de la regeneración nerviosa a través de los electrodos regenerativos implantados crónicamente entre los segmentos seccionados del nervio ciático de rata. Todos los animales implantados regeneran a través del electrodo. Sin embargo, entre los 6 y los 12 meses postimplante se observa un descenso en la reinervación funcional y en el número de axones regenerativos a nivel distal, posiblemente por una compresión axonal a nivel de las perforaciones del electrodo. Otro de los resultados del primer apartado, fue la observación de la menor proporción de axones motores que regeneran a través del electrodo, con respecto a los axones sensoriales. Estos datos se corroboran con los obtenidos con el recuento de neuronas que regeneran a través del electrodo. Una vez demostrada la regeneración a través de este tipo de interfases, el siguiente objetivo fue la extracción de señales neurales por los electrodos regenerativos, mediante estímulos funcionales y eléctricos a nivel distal. Los resultados obtenidos muestran la dificultad en la obtención de señales neurales, dado que sólo en el 50 % de los casos se obtienen registros neurales. En unos casos se da rotura de la cinta que permite la unión con el conector externo debido, probablemente, a tracciones mecánicas, y en otros casos por la falta de regeneración y reinervación distal, hechos que sugieren la necesidad de mejorar en el diseño del electrodo y en buscar estrategias de mejora de la regeneración. Dado que el objetivo final del electrodo regenerativo es el ser implantado en un nervio amputado, nos planteamos evaluar la regeneración axonal en un modelo de amputación evitando la reinervación de las dianas distales y estudiar si los axones eran capaces de mantenerse funcionales crónicamente y si se podía modular la regeneración mediante el transplante de Células de Schwann (CS). Nuestros resultados muestran como los axones son capaces de regenerar y mantenerse de forma crónica aun sin la posibilidad de alcanzar sus tejidos diana. El transplante de CS de cultivo primario tiene efectos positivos sobre la regeneración y mantenimiento de los axones en el modelo de amputación pero no aumenta el grado de maduración axonal. En cambio, el transplante de CS de una linea inmortalizada es un impedimento para la regeneración en este modelo. És la sobreexpresión de GDNF por parte de estas células las que ejercen un efecto positivo sobre la regeneración. En el último apartado del presente trabajo se ha evaluado la regeneración axonal motora en diferentes modelos de lesión y reparación asi como la evaluación de la regeneración motora y sensorial tras implante de raiz ventral o dorsal. De los resultados obtenidos cabe destacar como se pierde la topografía típica del nervio ciático tras sección del mismo y como se relaciona esta pérdida de la fasciculación con los resultados obtenidos a nivel funcional. Por otra parte, el injerto de una raíz ventral entre los segmentos de un nervio seccionado favorece la regeneración motora en las fases tempranas mientras que el injerto de una raíz dorsal afecta positivamente a la regeneración sensorial.Regenerative electrodes are designed to interface a high number of nerve fibers by using an array of holes, with electrodes built around them, implanted between the severed stumps of a peripheral nerve. Applicability of regenerative electrodes is dependent on the success of axonal regeneration through the perforations or holes, the possibility of nerve damage from the mechanical load imposed by the electrode or from constrictive forces within the holes, and the biocompatibility of the components. In this work, we have evaluated the axonal regeneration through the regenerative electrodes implanted chronically between the severed stumps of the rat sciatic nerve. Results show that all the rats implanted with the sieve electrode had regenerated and reinnervated target organs. However, in a few cases decline of targer reinnervation and loss of regeneration nerve fibers was found from 6 to 12 months postimplantation, probably due to a compressive axonopathy. Motor axons regenerated scattered within minifascicles and the number of motor axons was markedly lower distally than proximally to the sieve electrode. These results are in relation with those obtained in the quantification of sensory neurons and motor neurons that regenerated through the sieve electrode. The next objective was the obtention of neural signals through the sieve electrode after functional and electrical stimulation of distal targets. Recordings were obtained from a low proportion of electrodes on the sieve in response to functional stimulation of the paw. Failures are mainly attributed to increase of the electrodes impedance and to breaks due to mechanical traction affecting the whole system during chronic implants.Next study was done to evaluated the long-term capabilities to maintain axonal regeneration in an experimental amputee model. Moreovere, we evaluated if it is possible to enhance axonal regeneration with Schwann cells (SCs) transplantation. Results showed that axons can sustain distal regenerated branches without degenerating for a long time and express functional features. A transplant of primary Schwann cells in the amputee model has positive effects, by stimulating the axonal growth response and the number of regenerating axons. SCs of an immortalized line are not able to induce axonal growth in a permisive environment such as the degenerated peripheral nerve. GDNF production by these cells favorably influences axonal regeneration. In the last work we evaluated motor nerve regeneration after peripheral nerve injury and strategies to improve selective nerve regeneration. Results showed that the normal fascicular architecture and fascicular pattern of motor axons are maintained after a sciatic nerve crush, but there are lost after nerve section and repair, when motor axons are scattered within small regenerated fascicles throughout the nerve. The loss of the fascicular organization signficantly correlates with the deficient recovery of motor function. Transplantation of a small predegeneraed nerve segment inside a silicone guide enhances axonal regeneration, leading to slightly faster and higher levels of target reinnervation. Regeneration of motor axons is promoted at early times by the motor graft, whereas reinnervation of sensory pathways is increased in the presence of the sensory graft

Novel genetic and molecular pathways in pulmonary arterial hypertension associated with connective tissue disease

Pulmonary Arterial Hypertension (PAH) is a severe complication of Connective Tissue Disease (CTD), with remarkable morbidity and mortality. However, the molecular and genetic basis of CTD-PAH remains incompletely understood. This study aimed to screen for genetic defects in a cohort of patients with CTD-PAH, using a PAH-specific panel of 35 genes. During recruitment, 79 patients were studied, including 59 Systemic Sclerosis patients (SSc) and 69 females. Disease-associated variants were observed in nine patients: 4 pathogenic/likely pathogenic variants in 4 different genes (TBX4, ABCC8, KCNA5 and GDF2/BMP9) and 5 Variants of Unknown Significance (VUS) in 4 genes (ABCC8, NOTCH3, TOPBP1 and CTCFL). One patient with mixed CTD had a frameshift pathogenic variant in TBX4. Two patients with SSc-PAH carried variants in ABCC8. A patient diagnosed with Systemic Lupus Erythematous (SLE) presented a pathogenic nonsense variant in GDF2/BMP9. Another patient with SSc-PAH presented a pathogenic variant in KCNA5. Four patients with SSc-PAH carried a VUS in NOTCH1, CTCFL, CTCFL and TOPBP1, respectively. These findings suggest that genetic factors may contribute to Pulmonary Vascular Disease (PVD) in CTD patients.Instituto de Salud Carlos III | Ref. PI 18/0123

Zika Virus Screening among Spanish Team Members After 2016 Rio de Janeiro, Brazil, Olympic Games

We evaluated the risk for the Spanish Olympic Team acquiring Zika virus in Rio de Janeiro, Brazil, during 2016. We recruited 117 team members, and all tested negative for Zika virus. Lack of cases in this cohort supports the minimum risk estimates made before the Games