Trasplante de glía envolvente olfatoria para reparar lesiones crónicas de la médula espinal de ratas adultas: de roedores a primates.

RESUMEN El trasplante de glía envolvente olfatoria (OEG) se ha convertido en una de las estrategias experimentales más prometedoras para reparar los diferentes tipos de lesión de la médula espinal de mamíferos. Estas células promueven la recuperación funcional y la regeneración axonal en ratas adultas con lesiones medulares traumáticas de diferente gravedad. En la primera parte de este trabajo nos hemos centrado en el estudio, in vivo, del efecto de la OEG de rata adulta como terapia reparadora en la fase subaguda (un mes post-lesión) y crónica (cuatro meses) de la lesión medular. Puesto que todavía no se ha encontrado ninguna estrategia reparadora que permita mejorar la situación de los pacientes con lesión de la médula espinal, existen muchos pacientes que se encuentran en fase crónica y que necesitan una terapia promotora de la regeneración en su estado. Además, si esta terapia aplicada en fase crónica llegara a su fase clínica, permitiría a los hospitales el poder realizar los trasplantes pasado un periodo y en el momento en que el paciente ya estuviera estabilizado. Por ello es necesario estudiar si las diferentes terapias que han sido aplicadas con éxito en la fase aguda de la lesión en experimentos animales, conservan su efectividad cuando son aplicadas en la fase crónica. Hemos demostrado que la OEG promueve tanto la recuperación funcional de ratas parapléjicas con sección medular completa, como la regeneración axonal de sus neuronas supraespinales, alcanzando el muñón caudal a la lesión, cuando el trasplante se retrasa hasta cuatro meses post-lesión. La recuperación funcional e histológica fue significativamente superior que en los animales no trasplantados, indicando que al menos durante 4 meses después de la lesión, las neuronas lesionadas conservan la capacidad de responder a estrategias promotoras del crecimiento. Además hemos diseñado un método de trazado que nos permite contabilizar todas aquellas neuronas supraespinales que fueron capaces de regenerar su axón a través de la zona de la lesión y de penetrar en el muñón caudal. Mediante esta técnica de trazado hemos detectado regeneración en neuronas del núcleo rojo, rafe, vestibular, de la formación reticular y del locus coeruleus, todos ellos involucrados en la iniciación y el mantenimiento de la postura durante la locomoción voluntaria. El hecho de poder retrasar los trasplantes de OEG hasta 4 meses sin observar pérdidas en su capacidad promotora de la regeneración, garantiza la disponibilidad del tiempo requerido para la extracción del bulbo olfatorio, la puesta en cultivo, propagación y preparación de la OEG para poder aplicar esta terapia de forma autóloga, permitiendo a su vez la estabilización de los pacientes en el caso de su traslado a la clínica. Además hemos diseñado un sistema de estabilización de la columna vertebral mediante puentes fabricados con cemento dental. Estos puentes resultaron ser inocuos, disminuyeron el porcentaje de animales que desarrolló escoliosis y promovieron cierto grado de recuperación funcional espontánea en animales que no recibieron trasplante de OEG. Sin embargo, esta recuperación siempre fue significativamente inferior a la que se observó en animales que recibieron trasplantes de OEG. Finalmente, otro de los objetivos fundamentales de este trabajo ha sido el estudio in vitro de la OEG de primate no-humano, por su mayor proximidad filogenética a los humanos, y su comparación con la de roedor, cuya capacidad promotora de la regeneración ya ha sido demostrada. En este trabajo se han presentado evidencias que muestran por primera vez, que la OEG se puede obtener a partir de bulbos olfatorios de primates adultos mediante bulbectomías unilaterales, y que un solo bulbo olfatorio proporciona suficiente OEG fenotípicamente adecuada para una terapia celular segura, mediante trasplantes autólogos o heterólogos en primates. __________________________________________________________________________________________________Olfactory bulb Ensheathing Glia (OB-OEG) promote functional recovery and histological repair when transplanted immediately after spinal cord injury. We have checked in rats, if OB-OEG transplantation is also efficient when transplanted at subacute and chronic injury stages after complete spinal cord transection. OB-OEG were grafted at either one (subacute) or four (chronic) months post-lesion. During seven months following transplantation, rats from both OEG-transplanted groups presented a significant progressive improvement of motor function in the climbing test, not observed in non-grafted animals. OB-OEG grafts were equally efficient at subacute or chronic stages. Quantitative analysis by peroxidase tracing revealed that, in transplanted animals, axons of brainstem spinal cord-projecting neurons grew beyond the caudal stump border. Axons from neurons located in red nucleus, reticular formation, locus coeruleus, vestibular and raphe nuclei crossed the scar and regenerated distally in the spinal cord. The number of regenerating neurons was significantly higher in every transplanted group (subacute and chronic) than in the non-transplanted one, but transplanted groups did not differ one another. A positive linear correlation was found between the functional recovery of the animals and the number of brainstem regenerating neurons. OB-OEG transplantation can be delayed up to four months. This provides enough time to obtain and grow OEG for autologous use and also for patient stabilization before transplantation. To provide insight into the feasibility of OB-OEG use in human therapy, we studied in other close primates the suitability of these cells for this purpose. We demonstrated that OEG can be obtained from olfactory bulbs of adult macaca monkeys. However, unlike from rodent, primate OB-OEG are non-senescent, exhibit longer lifespan, are less sensitive to culture shock, and preserve for 2.5 months in vitro a phenotype suitable for grafting. One single macaca olfactory bulb gives in short-term enough OEG to guarantee autologous transplantation at the acute stage, and moreover, after long-term cultures may yield 20 thousand million OEG for storage in banks of cells for further use. Therefore, adult olfactory bulbs from macacas constitute a reliable source of OEG for cell therapy, and autologous transplantation of these cells is a viable approach in adult primates

On the Elimination of Infections Related to Oncogenic Human Papillomavirus: an Approach using a Computational Network Model

[EN] Cervical cancer is the fourth most common malignancy in women worldwide, although it is preventable with prophylactic HPV vaccination. HPV transmission-dynamic models can predict the potential for the global elimination of cervical cancer. The random network model is a new approach that allows individuals to be followed, and to implement a given vaccination policy according to their clinical records. We developed an HPV transmission-dynamic model on a lifetime sexual partners network based on individual contacts, also accounting for the sexual behavior of men who have sex with men (MSM). We analyzed the decline in the prevalence of HPV infection in a scenario of 75% and 90% coverage for both sexes. An important herd immunity effect for men and women was observed in the heterosexual network, even with 75% coverage. However, HPV infections are persistent in the MSM population, with sustained circulation of the virus among unvaccinated individuals. Coverage around 75% of both sexes would be necessary to eliminate HPV-related conditions in women within five decades. Nevertheless, the variation in the decline in infection in the long term between a vaccination coverage of 75% and 90% is relatively small, suggesting that reaching coverage of around 70-75% in the heterosexual network may be enough to confer high protection. Nevertheless, HPV elimination may be achieved if men's coverage is strictly controlled. This accurate representation of HPV transmission demonstrates the need to maintain high HPV vaccination coverage, especially in men, for whom the cost-effectiveness of vaccination is questioned.This work has been supported by the Spanish Ministerio de Economia, Industria y Competitividad (MINECO), the Agencia Estatal de Investigacion (AEI) and Fondo Europeo de Desarrollo Regional (FEDER UE), grant MTM2017-89664-P. Authors also wish to acknowledge Maria Giovanna Ferrario, Victor Latorre, and the Medical Statistics Consulting team (Valencia, Spain) for their collaboration in writing this manuscript.Muñoz-Quiles, C.; Diez-Domingo, J.; Acedo, L.; Sánchez-Alonso, V.; Villanueva Micó, RJ. (2021). On the Elimination of Infections Related to Oncogenic Human Papillomavirus: an Approach using a Computational Network Model. Viruses. 13(5):1-12. https://doi.org/10.3390/v13050906S11213

Brand-specific influenza vaccine effectiveness estimates during 2019/20 season in Europe – Results from the DRIVE EU study platform

DRIVE (Development of Robust and Innovative Vaccine Effectiveness) is an IMI funded public–private platform that aims to annually estimate brand-specific influenza vaccine effectiveness (IVE), for public health and regulatory purposes. IVE analyses and reporting are conducted by public partners in the con- sortium. In 2019/20, four primary care-based test-negative design (TND) studies (Austria, England, Italy (n = 2)), eight hospital-based TND studies (Finland, France, Italy, Romania, Spain (n = 4)), and one population- based cohort study (Finland) were conducted. The COVID-19 pandemic affected influenza surveillance in all participating study sites, therefore the study period was truncated on February 29, 2020. Age- stratified (6 m-17y, 18-64y, !65y), confounder-adjusted, site-specific adjusted IVE estimates were calcu- lated and pooled through meta-analysis. Parsimonious confounder-adjustment was performed, adjusting the estimates for age, sex and calendar time. TND studies included 3531 cases (351 vaccinated) and 5546 controls (1415 vaccinated) of all ages. IVE estimates were available for 8/11 brands marketed in Europe in 2019. Most children and adults < 64y were captured in primary care setting and the most frequently observed vaccine brand was Vaxigrip Tetra. The estimate against any influenza for Vaxigrip Tetra in primary care setting was 61% (95%CI 38–77) in children and 32% (95%CI 13–59) in adults up to 64y. Most adults ! 65y were captured in hospital setting and the most frequently observed brand was Fluad, with an estimate of 52% (95%CI 27–68)

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

Risk and impact of herpes zoster among COPD patients: a population-based study, 2009–2014

Abstract Background The objective of this study was to assess the incidence of Herpes Zoster (HZ) among patients with chronic obstructive pulmonary disease (COPD) and the impact of HZ on the underlying COPD. Methods A retrospective cohort of all subjects older than 49 years was followed up between 2009 and 2014 using population and health databases of Valencia Region (Spain). HZ and COPD were identified using ICD-9 codes, differentiating COPD patients with inhaled corticosteroids prescriptions (COPD-ICS). The incidence of HZ was compared among 3 groups [non-COPD, COPD and COPD-ICS populations] and use of healthcare resource due to HZ for 6 months following HZ diagnosis through different statistical generalized linear models (GLM). We also compared resources consumption due to COPD before and after HZ. Results The cohort consisted of 2,289,485 subjects, including 161,317 COPD patients of which 29,708 were COPD-ICS. HZ incidence rates were 11 (95% confidence interval [CI]: 10.7–11.4) and 13 (95% CI: 12.3–13.8) cases/1000 persons-year for COPD and COPD-ICS populations respectively. Incidence increased with age in all groups. The risk of HZ rose by 45 and 61% among COPD and COPD-ICS patients respectively compared to non-COPD (95% credible intervals [CrI]: 1.41–1.5 and 1.52–1.71 respectively). COPD patients consumed more resources due to their HZ than non-COPD. There was no statistically significant impact of the HZ on the resources consumed due to COPD during the 6 months post-HZ compared to the 6 months pre-HZ. Conclusions The presence of COPD increases the risk, severity and impact of zoster episodes

Adult olfactory bulbs from primates provide reliable ensheathing glia for cell therapy

The definitive version is available at http://www3.interscience.wiley.com/cgi-bin/fulltext/117905156/PDFSTARTOlfactory bulb ensheathing glia (OB-OEG) from adult rodents promote functional and morphological repair after grafting into injured spinal cords. To provide insight into the feasibility of using OB-OEG in human therapy, we studied OB-OEG in primates to determine their suitability for spinal cord transplantation. Here we show that OEG can be obtained from olfactory bulbs of adult macaca mulatta and nemestrina monkeys and compare their characteristics to those obtained from rats. In contrast to rodent OBOEG, primate OB-OEG are non-senescent, exhibit a longer lifespan, are less sensitive to high oxygen culture environment, and maintain a phenotype suitable for grafting for up to 2.5 months in vitro. Three-week cultures (short term) derived from a single macaca olfactory bulb provide enough OEG for autologous transplantation at the acute stage of injury, and after long-term cultures (2.5 months) may yield an additional 20 billion. OEG can be frozen for later use. Therefore, primate adult olfactory bulbs constitute a reliable source of OEG for cell therapy, and successful culture of these cells make autologous transplantation feasible.This work was supported by the Health Department of the Autonomous Government of Castilla y León. This work was supported by Fundación "La Caixa" (00/080), Ministry of Education and Science (SAF2001-2242), Fundación Investigación en Regeneración del Sistema Nervioso and Fundación Ramón Areces.Peer reviewe

Letter to the editor regarding “The role of age-sex interaction in the development of post-herpetic neuralgia”

The objective of the study was to evaluate the role of age and sex and their combined effect in the development of post-herpetic neuralgia (PHN) in a large population-based study, in order to confirm the results published previously by Amicizia et al. Data were extracted from population and healthcare databases from the Valencia Region (2009–2014). Logistic regressions were implemented to estimate the effect of increasing age on the probability of developing PHN stratified by sex. From a cohort of 2,289,485 subjects ≥ 50 years, 87,086 cases of HZ were registered and 13,658 (15.7%) of them developed PHN. In our population, PHN cases were more common in women and rose with increasing age independently of the sex

Lack of impact of rotavirus vaccines on seizure-related hospitalizations in children under 5 years old in Spain

Introduction: Up to date the impact of rotavirus (RV) vaccines on seizures has been poorly evaluated, with some studies but not all, showing different degrees of protection. Objectives: To assess the impact of RV vaccines on convulsions-related hospitalizations among children under 5 years of age residing in the Region of Valencia, Spain. Methods: A population-based, ecological study using the hospital discharge record (MBDS), the population-based administrative database (SIP) and the vaccine register (SIV), among Valencia Region's children <5 years old, during 2003 – 2015. Impact of vaccination on seizures-related hospitalization rates (780.3* ICD-9-MC code) was estimated by a multivariate Bayesian mixed Poisson regression model. Results: Since RV vaccines licensure in 2007, its coverage rate increased up to around 42%. When the impact of vaccination against seizures was controlled for potential confounders in the multivariate analysis, there was a non-statistically significant protective effect. Conclusions: We could not find any impact of RV vaccine coverage on seizure-related hospitalizations in children <5 years

Risk and impact of herpes zoster on patients with diabetes: A population-based study, 2009–2014

Aims: This study was designed to assess the impact of diabetes on the risk and severity of herpes zoster (HZ), and the impact of HZ on diabetes. It focused primarily on immunocompetent patients aged ≥ 50 years who would be eligible for preventive vaccination. Methods: Using population and healthcare databases of Valencia Region (Spain), a retrospective cohort of all subjects ≥ 50 years was followed up between 2009 and 2014. HZ and diabetes were defined using ICD-9 codes. We compared the incidence of HZ between non-diabetes and diabetes groups and healthcare resource consumption due to HZ in the 6 months following HZ diagnosis using different statistical generalized linear models (GLM). We also compared resources consumption due to diabetes treatment and haemoglobinA1c(HbA1c) levels before and after HZ. Results: The cohort consisted of 2,289,485 individuals ≥ 50 years old, 397,940 of whom had diabetes. HZ incidence rate was 9.3 cases/1000 persons with diabetes-year (95% CI: 9.1–9.4). Incidence increased with age in all groups. The risk of HZ increased in the diabetes group compared to the non-diabetes group (RR 1.2, 95% credibility interval [CrI] 1.17–1.22). Patients with diabetes utilized more health care resources due to their HZ episodes than patients without diabetes. In 24% of well controlled patients with diabetes (HbA1C levels ≤ 6.5%), HbA1C increased after HZ. Conclusions: Diabetes increased by 20% the risk of HZ. HZ contributed to the deterioration of glycaemic control and higher healthcare resource consumption in people with diabetes, becoming a priority population for HZ immunization

Additional file 1: of Risk and impact of herpes zoster among COPD patients: a population-based study, 2009–2014

Medication registered for HZ and PHN (ATC codes). Table listing the ATC codes, drug type and drug name of the medication registered for HZ and PHN. (DOCX 14 kb