Human adipose stem cell-conditioned medium increases survival of Friedreich's Ataxia cells submitted to oxidative stress

Friedreich's ataxia (FA) is a multisystemic disorder characterized by progressive gait, ataxia, and cardiomyopathy. There are few treatments for this disease; thus, we analyzed in vitro the possible beneficial effect of adult stem cells in FA. To this end, human adipose stem cells from healthy individuals and periodontal ligament cells from FA patients were isolated and cultured. FA cells are especially vulnerable to oxidative stress; thus, they were submitted to this condition and cultured in adipose stem cell-conditioned medium. This resulted in increased cell survival and upregulation of oxidative-stress-related genes as well as frataxin, among other genes. A number of trophic factors were shown to be expressed by the adipose stem cells, especially brain-derived neurotrophic factor (BDNF), which was also identified in the conditioned medium. The culture of the ataxic cells under oxidative stress and in the presence of this trophic factor confirmed its protective effect. Thus, this work demonstrates that adipose stem cell-conditioned medium from healthy individuals is capable of changing the transcription levels of oxidative-stress-related genes in cells that are particularly susceptible to this condition, avoiding cellular degeneration. Also, this work shows how neurotrophic factors, particularly BDNF, are capable of increasing cell survival in response to oxidative stress, which occurs in many neurodegenerative diseases. © Copyright 2012, Mary Ann Liebert, Inc. 2012.This work has been financed by EUCOMMTOOLS, Science and Innovation Ministry (MICINN BFU-2008-00588, CONSOLIDER CSD2007-00023), Valencian government (PROMETEO/2009/028), Cell Therapy Network-Carlos III Health Institute (RD06/0010/0023), Alicia Koplowitz Foundation, Granada Foundation of Friedreich’s Ataxia, 5P- Syndrome Foundation, and Diógenes Foundation/Elche (CATEDRA ELA).Peer Reviewe

Sistemas de Información Geográfica en Salud Pública: su aplicación al programa de vigilancia y control de la legionelosis

This experience has been developed by the Public Health Institute of the Community of Madrid in order to use the GIS tools in the Legionnaires’ disease prevention programme and specifically in three work areas: epidemiologic surveillance, cooling towers environmental control and plans of intervention in case of an outbreak of Legionnaires’ disease.After having considered different strategies with their advantages the selected model have been the use of map viewers in the intranet with a different configuration format depending on its goals: images map viewers for systematic non-outbreak cases and cooling towers surveillance, viewers that allow an easier and usual consultation and, in the other hand, layers map viewers, better adapted to more complex users’ necessities and so designed to work in emergency situations. Both models are implemented to decentralise the use of these indispensable tools and make them closer of the public health professionals.Some methodological proposals to study spatial association of Legionaires’disease outbreaks are also presented and discussed in this paper.Se presenta la experiencia desarrollada en el Instituto de Salud Pública de la Comunidad de Madrid en el manejo y aplicación de los SIG al programa de legionelosis en tres campos específicos e interrelacionados: la vigilancia de casos esporádicos, la vigilancia sanitario-ambiental de las instalaciones de riesgo y la intervención ante situaciones de alerta en salud pública.Se hace una revisión de los diferentes modelos operativos que se pueden aplicar, sus ventajas e inconvenientes, así como los modelos elegidos en este caso: el uso de visores cartográficos difundidos internamente en la organización vía web, de diferente configuración según su uso en la vigilancia sistemática (tanto de casos como de factores de riesgo medioambiental) o en la atención a situaciones de brotes comunitarios. En el primer caso se ha optado por visores cerrados, de imágenes, que facilitan la consulta sistemática de la situación y en el segundo, por visores de capas, más flexibles en su manejo. En ambos casos se persigue descentralizar el uso de las herramientas imprescindibles por parte de los técnicos de salud pública que trabajan en el territorio.Se revisa asimismo la estructura organizativa puesta en marcha para cumplir los objetivos en la forma diseñada.Por último, se formulan como propuestas metodológicas de abordaje del estudio espacial de brotes las diseñadas a lo largo de la experiencia que se presenta en este artículo

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

© The Author(s) 2019.A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.This work was supported by: SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER) to B.C.F., PI16/00156 (isciii and FEDER) to J.P.V., LUCHAMOS POR LA VIDA project to F.R.J. and J.P.V., SAF2017-83702-R (MINECO and FEDER), Red TERCEL RD12/0019/0024 (ISCIII) and GVA-PROMETEO 2018/041 (Generalitat Valenciana) to S.M. J.P.V. is supported by the RyC research programme (RYC-2013-14097) and F.R.J. by the predoctoral research programme (BES-2014-070615), from MINECO and FEDER

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.Acknowledgements: We are highly indebted to the participants and their families for their cooperation in this study. We also thank IDIVAL biobank (Inés Santiuste and Jana Arozamena) for clinical samples and data as well as the PAFIP members (Marga Corredera) for the data collection. This work was supported by: SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER) to B.C.F., PI16/00156 (isciii and FEDER) to J.P.V., LUCHAMOS POR LA VIDA project to F.R.J. and J.P.V., SAF2017-83702-R (MINECO and FEDER), Red TERCEL RD12/0019/0024 (ISCIII) and GVA-PROMETEO 2018/041 (Generalitat Valenciana) to S.M. J.P.V. is supported by the RyC research programme (RYC-2013-14097) and F.R.J. by the predoctoral research programme (BES-2014-070615), from MINECO and FEDER

Análise espacial de um surto de leishmaniose no sul da área metropolitana de Madrid. 2009-2013

Leishmaniasis is an endemic zoonotic disease in Spain. The purpose of this study is to conduct a spatial analysis of the key elements of this disease’s cycle–vectors, reservoirs and human cases–during a community outbreak in four towns in the southern corner of Madrid’s metropolitan area: Fuenlabrada, Getafe, Humanes de Madrid and Leganés.A total of 485 cases of leishmaniasis, registered in the Community of Madrid’s Epidemiological Surveillance System were analyzed; symptoms were reported between July 1, 2009 and June 30, 2013.Most cases were reported in northern Fuenlabrada. The results of spatial analysis revealed that, during the study period, the areas with the highest concentration of cases were peripheral residential areas bordering green zones with high densities of sandflies and a relatively high prevalence of leishmaniasis in lagomorphs. This shows that the main exposure occurred at home or close to home.This study shows that road and railway infrastructures could have played a decisive role in the spatial pattern of the outbreak by acting as territorial barriers somewhat isolating several urban centers from exposure to the pathogen, as routes of entry for the vector into other urban centers, or as generators of an environment (slopes on roadside) of suitable habitats for reservoirs and vectors.The spatial analysis of the outbreak has guided the actions for preventing and controlling the outbreak in these towns and is still useful to study its evolution. GISs are tools that help to understand the genesis and evolution of infectious disease outbreaks and to design the appropriate environmental interventions.La leishmaniasis es una enfermedad zoonótica endémica en España. El objetivo de este estudio es realizar un análisis espacial de los elementos claves del ciclo de la enfermedad, vectores, reservorios y casos humanos, en un brote comunitario declarado en cuatro municipios del sur del Área metropolitana de Madrid: Fuenlabrada, Getafe, Humanes de Madrid y Leganés.Se analizaron 485 casos de leishmaniasis, declarados en el Sistema de Vigilancia Epidemiológica de la Comunidad de Madrid, con fecha de inicio de síntomas entre el 1 de julio de 2009 y el 30 de junio de 2013.La mayor parte de los casos se localizaron en el norte de Fuenlabrada. Los resultados del análisis espacial pusieron de manifiesto que, durante el periodo de estudio, la zona con mayor concentración de casos coincidió espacialmente con áreas residenciales periféricas inmediatas a espacios verdes con alta densidad de flebotomos y prevalencia relativamente elevada de leishmaniasis en lagomorfos. Esto informa de que la exposición principal ocurre en su entorno domiciliario o peridomiciliario.El estudio parece indicar que las infraestructuras viarias podrían haber tenido un papel decisivo en la distribución espacial del brote comportándose de diferentes maneras: barreras territoriales que aíslan en cierta medida a varios núcleos urbanos de la exposición al patógeno, vías de penetración del vector en el interior de otros núcleos o generadores de un entorno de hábitats idóneos para reservorios y vectores.El análisis espacial ha permitido orientar las actuaciones de prevención y control del brote y continúa siendo de gran utilidad en la evolución del mismo. Los sistemas de información geográfica son herramientas que ayudan a la comprensión de la génesis y evolución de los brotes de enfermedades infecciosas, así como al diseño de las intervenciones ambientales.A leishmaniose é uma zoonose endémica em Espanha. O objetivo deste estudo é realizar uma análise espacial dos elementos-chave do ciclo da doença: vetores, reservatórios e casos humanos num surto declarado em quatro municípios da região metropolitana do Sul de Madrid: Fuenlabrada, Getafe, Humanes de Madrid e Leganés.Foram analisados 485 casos de leishmaniose declarados através do Sistema de Vigilância Epidemiológica da Comunidade de Madrid, com data de início de sintomas entre 1 de julho de 2009 e 30 de junho de 2013.A maioria dos casos foi encontrada no norte de Fuenlabrada. A análise espacial revelou que, durante o período de estudo, as áreas com a maior concentração de casos foram áreas residenciais periféricas perto de zonas verdes com alta densidade de flebótomo e prevalência relativamente alta de leishmaniose em lagomorfos, indicando que a exposição ocorre principalmente no domicílio ou no peridomicílio.O estudo sugere que as infraestruturas rodoviárias e ferroviárias poderiam ter desempenhado um papel decisivo no comportamento espacial do surto de diferentes formas: como uma barreira territorial isolando vários centros urbanos da exposição ao agente patogénico; como uma via de entrada do vetor noutros nos centros urbanos; ou como geradores de habitats adequados para reservatórios e vetores (encostas na beira da estrada).A análise espacial do fenómeno tem norteado as ações de prevenção e controle do surto nos municípios afetados e continua a ser útil no seguimento da evolução do mesmo. Os sistemas de informação geográfica são ferramentas que ajudam à compreensão da génese e evolução dos surtos de doenças infeciosas, assim como à definição das intervenções ambientais

Vascular pattern of the dentate gyrus is regulated by neural progenitors

Neurogenesis is a vital process that begins during early embryonic development and continues until adulthood, though in the latter case, it is restricted to the subventricular zone and the subgranular zone of the dentate gyrus (DG). In particular, the DG's neurogenic properties are structurally and functionally unique, which may be related to its singular vascular pattern. Neurogenesis and angiogenesis share molecular signals and act synergistically, supporting the concept of a neurogenic niche as a functional unit between neural precursors cells and their environment, in which the blood vessels play an important role. Whereas it is well known that vascular development controls neural proliferation in the embryonary and in the adult brain, by releasing neurotrophic factors; the potential influence of neural cells on vascular components during angiogenesis is largely unknown. We have demonstrated that the reduction of neural progenitors leads to a significant impairment of vascular development. Since VEGF is a potential regulator in the neurogenesis-angiogenesis crosstalk, we were interested in assessing the possible role of this molecule in the hippocampal neurovascular development. Our results showed that VEGF is the molecule involved in the regulation of vascular development by neural progenitor cells in the DG.This work was supported by Spanish State Research Agency, through the “Severo Ochoa” Program for Centers of Excellence in R&D (ref. SEV- 2013-0317), by Economy and Competitivity Ministry through Fondos FEDER (SAF2014-59347-C2-1-R), by Generalitat Valenciana Prometeo II Grant (2014/014), by Instituto de Salud Carlos III (RD16/001/0010) (Co-funded by European Regional Development Fund/European Social Fund) and Todos con Natalia Niemann Pick C Association (2016/00084/001).Peer reviewe

Stem cells from wildtype and Friedreich's ataxia mice present similar neuroprotective properties in dorsal root ganglia cells.

Many neurodegenerative disorders share a common susceptibility to oxidative stress, including Alzheimer's, Parkinson Disease, Huntington Disease and Friedreich's ataxia. In a previous work, we proved that stem cell-conditioned medium increased the survival of cells isolated from Friedreich's ataxia patients, when submitted to oxidative stress. The aim of the present work is to confirm this same effect in dorsal root ganglia cells isolated from YG8 mice, a mouse model of Friedreich's ataxia. In this disorder, the neurons of the dorsal root ganglia are the first to degenerate. Also, in this work we cultured mesenchymal stem cells isolated from YG8 mice, in order to compare them with their wildtype counterpart. To this end, dorsal root ganglia primary cultures isolated from YG8 mice were exposed to oxidative stress and cultured with conditioned medium from either wildtype or YG8 stem cells. As a result, the conditioned medium increased the survival of the dorsal root ganglia cells. This coincided with an increase in oxidative stress-related markers and frataxin expression levels. BDNF, NT3 and NT4 trophic factors were detected in the conditioned medium of both wild-type and YG8 stem cells, all which bind to the various neuronal cell types present in the dorsal root ganglia. No differences were observed in the stem cells isolated from wildtype and YG8 mice. The results presented confirm the possibility that autologous stem cell transplantation may be a viable therapeutic approach in protecting dorsal root ganglia neurons of Friedreich's ataxia patients

Ondas de choque y células madre mesenquimales como tratamiento en la fase aguda de la lesión medular: un estudio piloto

[EN]: [Introduction] Spinal cord injury (SCI) is a complex pathology with thousands of patients worldwide. During the acute early phase, neural tissue shows some regenerative properties that disappear at the chronic phase. Shock Waves and Stem Cells have been proposed as a possible therapy. [Methods] Here, we analyse Shock Waves’ immediate effect over spinal cord genetic response in the injured and healthy spinal cord and the effect of Shock Waves and combined Shock Waves plus Stem Cells distally grafted to treat the first month after spinal cord injury. [Results] The immediate application of shock waves increases VEGF (Vascular Endothelial Growth Factor) but reduces the BDNF (Brain-Derived Growth Factor) RNA (Ribonucleic acid) response. Shock wave therapy increases GFAP (Glial fibrillary acidic protein) positive cells and vascularity during the treatment's acute phase. [Conclusion] Shock wave treatment seems to be enough to produce benefits in the acute phase of spinal cord injury, with no accumulative positive effects when mesenchymal stem cell graft is applied together.[ES]: [Introducción] La lesión medular es una afección compleja con miles de pacientes repartidos a lo largo del mundo. Durante la fase aguda temprana de la lesión, el tejido neural muestras ciertas propiedades regenerativas que desaparecen durante la fase crónica. Las ondas de choque y las células madre han sido propuestas como posibles terapias. [Metodología] En este estudio analizamos el efecto inmediato de una sesión de ondas de choque sobre la médula espinal, tanto sana como lesionada, y si su efecto es sumatorio al que produce un tratamiento de células madre mesenquimales inyectadas distalmente, como se ha observado en estudios previos. [Resultados] Se observa un efecto inmediato con las ondas de choque que promueve un incremento del efecto trófico vascular endotelial, y una disminución del factor trófico derivado del cerebro. La terapia prolongada con ondas de choque en la fase aguda incrementa la presencia de astrocitos y la vascularización local. No parece haber efecto sumatorio con el tratamiento de células madre, produciéndose efectos similares con o sin las células madre mesenquimales. [Conclusiones] Las ondas de choque parecen tener un efecto positivo durante la fase aguda de una lesión medular por compresión, sin que el tratamiento distal de células madre mesenquimales parezca implicar un efecto sumatorio.Salvador Martínez acknowledges financial support from the Spanish State Research Agency, through the “Severo Ochoa” Programme for Centres of Excellence in R&D (ref. SEV-2013-0317), Generalitat Valenciana PROMETEO2018/041, and also has been funded by Instituto de Salud Carlos III through the project “RD16/001/0010” (Co-funded by European Regional Development Fund/European Social Fund) “Investing in your future”), and CIBERSAM.Peer reviewe

Stem cell injection in the hindlimb skeletal muscle enhances neurorepair in mice with spinal cord injury

[Aims]: To develop a low-risk, little-invasive stem cell-based method to treat acute spinal cord injuries. methods: Adult mice were submitted to an incomplete spinal cord injury, and mesenchymal stem cells injected intramuscularly into both hindlimbs. Behavior tests and MRI of the spinal cord were periodically performed for up to 6 months, along with immunohistochemical analysis. Immunohistochemical and PCR analysis of the muscles were used to detect the grafted cells as well as the soluble factors released.[Results]: The stem cell-treated mice presented significant improvements in their motor skills 5 months after treatment. Spinal cord repair was detected by magnetic resonance and immunohistochemistry. In the hindlimb muscles, the stem cells activated muscle and motor neuron repair mechanisms, due to the secretion of several neurotrophic factors.[Conclusion]: Bone marrow mesenchymal stem cell injection into hindlimb muscles stimulates spinal cord repair in acute spinal cord lesions.Peer reviewe