Estudio clínico y de neuroimagen funcional de la afasia progresiva primaria y otras demencias de inicio focal

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Medicina, leída el 02-12-2013Depto. de MedicinaFac. de MedicinaTRUEunpu

Notch Signalling in the Hippocampus of Patients With Motor Neuron Disease

IntroductionThe Notch signalling pathway regulates neuronal survival. It has some similarities with the APP signalling pathway, and competes with the latter for α- and γ-secretase proteolytic complexes. The objective of this study was to study the Notch signalling pathway in the hippocampi of patients with motor neuron disease.MethodsWe studied biological material from the autopsies of 12 patients with motor neuron disease and 4 controls. We analysed the molecular markers of the Notch and APP signalling pathways, TDP43, tau, and markers of neurogenesis.Results and ConclusionLow NICD expression suggests Notch signalling pathway inactivation in neurons. Inactivation of the pathway despite increased Notch1 expression is associated with a lack of α-secretase expression. We observed increased β-secretase expression associated with activation of the amyloid cascade of APP, leading to increases in amyloid-β and AICD peptides and decreased levels of Fe65. Inactivation of the Notch signalling pathway is an important factor in decreased neurogenic response in the hippocampi of patients with amyotrophic lateral sclerosis

Wallenberg’s syndrome and symptomatic trigeminal neuralgia

Symptomatic trigeminal neuralgia due to a brainstem infarction is said to be rare. However, facial pain is not uncommon in Wallenberg’s syndrome. Facial pain related to a Wallenberg’s syndrome may be either persistent of intermittent, and occasionally occurs in brief attacks. Here, we report a patient with a right lateral medullary infarction who started having first division trigeminal neuralgia 1 month after the stroke. The pain paroxysms were suppressed with gabapentin

Traumatismo de la fisis distal de la tibia: tratamiento y resultados

Hemos realizado un estudio retrospectivo de 206 fracturas fisiarias distales de tibia. Se excluyeron las lesiones fisiarias aisladas de peroné y los arrancamientos óseos de tibia o peroné sin afectación de la placa fisiaria. Se recopilaron variables de 199 casos relativas al diagnóstico, tratamiento y evolución. La clasificación utilizada fue la de Salter y Harris para los traumatismos fisiarios. El tiempo de seguimiento medio fue de 7,73 meses (rango de 1,36 a 126 meses). Se trataba de 115 varones y 84 hembras. El tipo más frecuente fue el II (n=82, 41,2%). La media de edad fue de 12,1 ± 2,6 años. La causa más frecuente fue el accidente casual. Se realizó tratamiento conservador en 121 casos (60,8%). Los resultados se valoraron en función de las complicaciones aparecidas. En 169 casos (90,7%) el resultado fue satisfactorio, encontrando sólo 17 casos (9,3%) de malos resultados por presentar desalineación de los ejes (de 5 o más grados) y/o acortamiento (de 1 cm o más). Se presentó malposición en 9 casos (12%) en el tipo II, 4 casos (10,8%) en el tipo III, 1 caso (4%) en el tipo IV y 3 casos (100%) en el tipo V. La relación entre el grado de reducción obtenido y aparición de malposición sólo presentó diferencias significativas en los casos aparecidos del tipo II. La aparición de alteraciones de crecimiento en los tipos III y IV suele tener poca trascendencia clínica por ocurrir en pacientes con cartílagos en fase avanzada de cierre, no así en el tipo II donde pueden estar asociadas lesiones de tipo V, aconsejando realizar reducciones mediante maniobras cuidadosas para intentar evitar alteraciones.This is a retrospective study of 206 physeal fractures of the distal tibia. Isolated physeal injuries to the fibula and dislocations of the tibia or fibula without involvement of the growth plate were excluded. Variables from 199 cases relative to the diagnosis, treatment and evolution were recorded. The Salter-Harris classification was used for physeal fractures. The mean follow-up period was 7.73 months (range: 1.36 to 126 months), and 115 male and 84 female patients were treated. The most frequented type of fracture was type II (n=82, 41.2%). The mean age of the patients was 12.1 ± 2.6 years. The most frequented cause of injury was accident. In 121 cases (60.8%) the injury was treated conservatively. The results were evaluated in terms of subsequent complications. In 169 cases (90.7%) the results were satisfactory, and in only 17 cases (9.3%) the results were poor as a consequence of misalignment of the axes (5 or more degrees) and/or shortening (1 cm or more). Misalignment was found in 9 cases (12%) of type II, 4 cases (10.8%) of type III, 1 case (4%) of type IV and 3 cases (100%) of type V. The correlation between the degree of reduction obtained and the appearance of misalignment was statistically significant only in the cases of type II fracture. The appearance of growth disturbance in type III and type IV fractures is usually of minor clinical importance because it occurs in patients whose cartilage is at an advanced stage of closure, unlike type II fractures, which may be associated with type V injuries. In these cases reduction must be performed with special care in order to avoid growth disturbance

Biohybrids of scaffolding hyaluronic acid biomaterials plus adipose stem cells home local neural stem and endothelial cells: Implications for reconstruction of brain lesions after stroke.

[EN] Endogenous neurogenesis in stroke is insufficient to replace the lost brain tissue, largely due to the lack of a proper biological structure to let new cells dwell in the damaged area. We hypothesized that scaffolds made of hyaluronic acid (HA) biomaterials (BM) could provide a suitable environment to home not only new neurons, but also vessels, glia and neurofilaments. Further, the addition of exogenous cells, such as adipose stem cells (ASC) could increase this effect. Athymic mice were randomly assigned to a one of four group: stroke alone, stroke and implantation of BM, stroke and implantation of BM with ASC, and sham operated animals. Stroke model consisted of middle cerebral artery thrombosis with FeCl3. After 30 days, animals underwent magnetic resonance imaging (MRI) and were sacrificed. Proliferation and neurogenesis increased at the subventricular zone ipsilateral to the ventricle and neuroblasts, glial, and endothelial cells forming capillaries were seen inside the BM. Those effects increased when ASC were added, while there was less inflammatory reaction. Three-dimensional scaffolds made of HA are able to home newly formed neurons, glia, and endothelial cells permitting the growth neurofilaments inside them. The addition of ASC increase these effects and decrease the inflammatory reaction to the implant.Contract grant sponsor: CIBER BBN Contract grant sponsor: ERANET NEURON CALL; contract grant number: PRI-PIMNEU-2011-1372 Contract grant sponsor: Spanish Science & Innovation Ministery; contract grant number: MAT 2011-28791-C03-01, MAT 2011-28791-C03-02 an Contract grant sponsor: TERCEL; contract grant number: RD12/0019/0010 Contract grant sponsor: Spanish Ministry of Economy and Competitiveness through grants MAT2015-66666-C3, and DPI2015-72863-EXPSanchez-Rojas, L.; Gómez-Pinedo, U.; Benito-Martin, MS.; León-Espinosa, G.; Rascón-Ramirez, F.; Lendinez, C.; Martínez-Ramos, C.... (2019). Biohybrids of scaffolding hyaluronic acid biomaterials plus adipose stem cells home local neural stem and endothelial cells: Implications for reconstruction of brain lesions after stroke. Journal of Biomedical Materials Research Part B Applied Biomaterials. 107(5):1598-1606. https://doi.org/10.1002/jbm.b.34252S159816061075Azad, T. D., Veeravagu, A., & Steinberg, G. K. (2016). Neurorestoration after stroke. Neurosurgical Focus, 40(5), E2. doi:10.3171/2016.2.focus15637Faralli, A., Bigoni, M., Mauro, A., Rossi, F., & Carulli, D. (2013). Noninvasive Strategies to Promote Functional Recovery after Stroke. Neural Plasticity, 2013, 1-16. doi:10.1155/2013/854597Yamashita, T., Ninomiya, M., Hernandez Acosta, P., Garcia-Verdugo, J. M., Sunabori, T., Sakaguchi, M., … Sawamoto, K. (2006). Subventricular Zone-Derived Neuroblasts Migrate and Differentiate into Mature Neurons in the Post-Stroke Adult Striatum. Journal of Neuroscience, 26(24), 6627-6636. doi:10.1523/jneurosci.0149-06.2006Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., & Lindvall, O. (2002). Neuronal replacement from endogenous precursors in the adult brain after stroke. Nature Medicine, 8(9), 963-970. doi:10.1038/nm747Doeppner, T. R., & Hermann, D. M. (2015). Editorial: Stem cells and progenitor cells in ischemic stroke—fashion or future? Frontiers in Cellular Neuroscience, 9. doi:10.3389/fncel.2015.00334Zhang, Z. G., & Chopp, M. (2015). Promoting brain remodeling to aid in stroke recovery. Trends in Molecular Medicine, 21(9), 543-548. doi:10.1016/j.molmed.2015.07.005Crapo, P. M., Medberry, C. J., Reing, J. E., Tottey, S., van der Merwe, Y., Jones, K. E., & Badylak, S. F. (2012). Biologic scaffolds composed of central nervous system extracellular matrix. Biomaterials, 33(13), 3539-3547. doi:10.1016/j.biomaterials.2012.01.044Ju, R., Wen, Y., Gou, R., Wang, Y., & Xu, Q. (2014). The Experimental Therapy on Brain Ischemia by Improvement of Local Angiogenesis with Tissue Engineering in the Mouse. Cell Transplantation, 23(1_suppl), 83-95. doi:10.3727/096368914x684998Zhou, K., Motamed, S., Thouas, G. A., Bernard, C. C., Li, D., Parkington, H. C., … Forsythe, J. S. (2016). Graphene Functionalized Scaffolds Reduce the Inflammatory Response and Supports Endogenous Neuroblast Migration when Implanted in the Adult Brain. PLOS ONE, 11(3), e0151589. doi:10.1371/journal.pone.0151589Elias, P. Z., & Spector, M. (2012). Implantation of a collagen scaffold seeded with adult rat hippocampal progenitors in a rat model of penetrating brain injury. Journal of Neuroscience Methods, 209(1), 199-211. doi:10.1016/j.jneumeth.2012.06.003Tang, J. D., & Lampe, K. J. (2018). From de novo peptides to native proteins: advancements in biomaterial scaffolds for acute ischemic stroke repair. Biomedical Materials, 13(3), 034103. doi:10.1088/1748-605x/aaa4c3Nih, L. R., Carmichael, S. T., & Segura, T. (2016). Hydrogels for brain repair after stroke: an emerging treatment option. Current Opinion in Biotechnology, 40, 155-163. doi:10.1016/j.copbio.2016.04.021Moshayedi, P., Nih, L. R., Llorente, I. L., Berg, A. R., Cinkornpumin, J., Lowry, W. E., … Carmichael, S. T. (2016). Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain. Biomaterials, 105, 145-155. doi:10.1016/j.biomaterials.2016.07.028Lindvall, O., & Kokaia, Z. (2011). Stem Cell Research in Stroke. Stroke, 42(8), 2369-2375. doi:10.1161/strokeaha.110.599654Reis, C., Wilkinson, M., Reis, H., Akyol, O., Gospodarev, V., Araujo, C., … Zhang, J. H. (2017). A Look into Stem Cell Therapy: Exploring the Options for Treatment of Ischemic Stroke. Stem Cells International, 2017, 1-14. doi:10.1155/2017/3267352Ikegame, Y., Yamashita, K., Hayashi, S.-I., Mizuno, H., Tawada, M., You, F., … Iwama, T. (2011). Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy, 13(6), 675-685. doi:10.3109/14653249.2010.549122Wei, X., Zhao, L., Zhong, J., Gu, H., Feng, D., Johnstone, B. H., … Du, Y. (2009). Adipose stromal cells-secreted neuroprotective media against neuronal apoptosis. Neuroscience Letters, 462(1), 76-79. doi:10.1016/j.neulet.2009.06.054Gómez-Pinedo, U., Sanchez-Rojas, L., Benito-Martin, M. S., Lendinez, C., León-Espinosa, G., Rascón-Ramirez, F. J., … Barcia, J. A. (2018). Evaluation of the Safety and Efficacy of the Therapeutic Potential of Adipose-Derived Stem Cells Injected in the Cerebral Ischemic Penumbra. Journal of Stroke and Cerebrovascular Diseases, 27(9), 2453-2465. doi:10.1016/j.jstrokecerebrovasdis.2018.05.001Rodríguez-Pérez, E., Lloret Compañ, A., Monleón Pradas, M., & Martínez-Ramos, C. (2016). Scaffolds of Hyaluronic Acid-Poly(Ethyl Acrylate) Interpenetrating Networks: Characterization and In Vitro Studies. Macromolecular Bioscience, 16(8), 1147-1157. doi:10.1002/mabi.201600028Davoust, C., Plas, B., Béduer, A., Demain, B., Salabert, A.-S., Sol, J. C., … Loubinoux, I. (2017). Regenerative potential of primary adult human neural stem cells on micropatterned bio-implants boosts motor recovery. Stem Cell Research & Therapy, 8(1). doi:10.1186/s13287-017-0702-3Bateman, M. E., Strong, A. L., Gimble, J. M., & Bunnell, B. A. (2018). Concise Review: Using Fat to Fight Disease: A Systematic Review of Nonhomologous Adipose-Derived Stromal/Stem Cell Therapies. STEM CELLS, 36(9), 1311-1328. doi:10.1002/stem.2847Seo, J. H., Kim, H., Park, E. S., Lee, J. E., Kim, D. W., Kim, H. O., … Cho, S.-R. (2013). Environmental Enrichment Synergistically Improves Functional Recovery by Transplanted Adipose Stem Cells in Chronic Hypoxic-Ischemic Brain Injury. Cell Transplantation, 22(9), 1553-1568. doi:10.3727/096368912x662390Palma-Tortosa, S., García-Culebras, A., Moraga, A., Hurtado, O., Perez-Ruiz, A., Durán-Laforet, V., … Lizasoain, I. (2017). Specific Features of SVZ Neurogenesis After Cortical Ischemia: a Longitudinal Study. Scientific Reports, 7(1). doi:10.1038/s41598-017-16109-7Lu, J., Manaenko, A., & Hu, Q. (2017). Targeting Adult Neurogenesis for Poststroke Therapy. Stem Cells International, 2017, 1-10. doi:10.1155/2017/5868632Faiz, M., Sachewsky, N., Gascón, S., Bang, K. W. A., Morshead, C. M., & Nagy, A. (2015). Adult Neural Stem Cells from the Subventricular Zone Give Rise to Reactive Astrocytes in the Cortex after Stroke. Cell Stem Cell, 17(5), 624-634. doi:10.1016/j.stem.2015.08.002Moraga, A., Pradillo, J. M., García-Culebras, A., Palma-Tortosa, S., Ballesteros, I., Hernández-Jiménez, M., … Lizasoain, I. (2015). Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia. Journal of Neuroinflammation, 12(1). doi:10.1186/s12974-015-0314-8Oh, J. S., Park, I. S., Kim, K. N., Yoon, D. H., Kim, S.-H., & Ha, Y. (2012). Transplantation of an adipose stem cell cluster in a spinal cord injury. NeuroReport, 23(5), 277-282. doi:10.1097/wnr.0b013e3283505ae2Erba, P., Terenghi, G., & J. Kingham, P. (2010). Neural Differentiation and Therapeutic Potential of Adipose Tissue Derived Stem Cells. Current Stem Cell Research & Therapy, 5(2), 153-160. doi:10.2174/157488810791268645Grudzenski, S., Baier, S., Ebert, A., Pullens, P., Lemke, A., Bieback, K., … Fatar, M. (2017). The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate. 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Materials for Central Nervous System Tissue Engineering Cells and Biomaterials in Regenerative Medicine Daniel Eberli IntechOpen DOI: 10.5772/59339Wang, Y., Wei, Y. T., Zu, Z. H., Ju, R. K., Guo, M. Y., Wang, X. M., … Cui, F. Z. (2011). Combination of Hyaluronic Acid Hydrogel Scaffold and PLGA Microspheres for Supporting Survival of Neural Stem Cells. Pharmaceutical Research, 28(6), 1406-1414. doi:10.1007/s11095-011-0452-3Nih, L. R., Moshayedi, P., Llorente, I. L., Berg, A. R., Cinkornpumin, J., Lowry, W. E., … Carmichael, S. T. (2017). Engineered HA hydrogel for stem cell transplantation in the brain: Biocompatibility data using a design of experiment approach. Data in Brief, 10, 202-209. doi:10.1016/j.dib.2016.11.069Nih, L. R., Gojgini, S., Carmichael, S. T., & Segura, T. (2018). Dual-function injectable angiogenic biomaterial for the repair of brain tissue following stroke. Nature Materials, 17(7), 642-651. doi:10.1038/s41563-018-0083-8Lin, R., & Iacovitti, L. (2015). Classic and novel stem cell niches in brain homeostasis and repair. Brain Research, 1628, 327-342. doi:10.1016/j.brainres.2015.04.029Ruddy, R. M., & Morshead, C. M. (2017). Home sweet home: the neural stem cell niche throughout development and after injury. Cell and Tissue Research, 371(1), 125-141. doi:10.1007/s00441-017-2658-0Mora-Lee, S., Sirerol-Piquer, M. S., Gutiérrez-Pérez, M., Gomez-Pinedo, U., Roobrouck, V. D., López, T., … García-Verdugo, J. M. (2012). Therapeutic Effects of hMAPC and hMSC Transplantation after Stroke in Mice. PLoS ONE, 7(8), e43683. doi:10.1371/journal.pone.0043683Boisserand, L. S. B., Kodama, T., Papassin, J., Auzely, R., Moisan, A., Rome, C., & Detante, O. (2016). Biomaterial Applications in Cell-Based Therapy in Experimental Stroke. Stem Cells International, 2016, 1-14. doi:10.1155/2016/6810562Adams, A. M., Arruda, E. M., & Larkin, L. M. (2012). Use of adipose-derived stem cells to fabricate scaffoldless tissue-engineered neural conduits in vitro. Neuroscience, 201, 349-356. doi:10.1016/j.neuroscience.2011.11.004Le Friec, A., Salabert, A.-S., Davoust, C., Demain, B., Vieu, C., Vaysse, L., … Loubinoux, I. (2017). Enhancing Plasticity of the Central Nervous System: Drugs, Stem Cell Therapy, and Neuro-Implants. Neural Plasticity, 2017, 1-9. doi:10.1155/2017/2545736Traystman, R. J. (2003). Animal Models of Focal and Global Cerebral Ischemia. ILAR Journal, 44(2), 85-95. doi:10.1093/ilar.44.2.85Doeppner, T. R., Kaltwasser, B., Teli, M. K., Sanchez-Mendoza, E. H., Kilic, E., Bähr, M., & Hermann, D. M. (2015). Post-stroke transplantation of adult subventricular zone derived neural progenitor cells — A comprehensive analysis of cell delivery routes and their underlying mechanisms. Experimental Neurology, 273, 45-56. doi:10.1016/j.expneurol.2015.07.023Karatas, H., Erdener, S. E., Gursoy-Ozdemir, Y., Gurer, G., Soylemezoglu, F., Dunn, A. K., & Dalkara, T. (2011). 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Metabolomic Analysis Points to Bioactive Lipid Species and Acireductone Dioxygenase 1 (ADI1) as Potential Therapeutic Targets in Poor Prognosis Endometrial Cancer

Metabolomic profiling analysis has the potential to highlight new molecules and cellular pathways that may serve as potential therapeutic targets for disease treatment. In this study, we used an LC-MS/MS platform to define, for the first time, the specific metabolomic signature of uterine serous carcinoma (SC), a relatively rare and aggressive variant of endometrial cancer (EC) responsible for 40% of all endometrial cancer-related deaths. A metabolomic analysis of 31 ECs (20 endometrial endometrioid carcinomas (EECs) and 11 SCs) was performed. Following multivariate statistical analysis, we identified 232 statistically different metabolites among the SC and EEC patient samples. Notably, most of the metabolites identified (89.2%) were lipid species and showed lower levels in SCs when compared to EECs. In addition to lipids, we also documented metabolites belonging to amino acids and purine nucleotides (such as 2-Oxo-4-methylthiobutanoic acid, synthesised by acireductone dioxygenase 1 (ADI1) enzyme), which showed higher levels in SCs. To further investigate the role of ADI1 in SC, we analysed the expression protein levels of ADI1 in 96 ECs (67 EECs and 29 SCs), proving that the levels of ADI1 were higher in SCs compared to EECs. We also found that ADI1 mRNA levels were higher in p53 abnormal ECs compared to p53 wild type tumours. Furthermore, elevated ADI1 mRNA levels showed a statistically significant negative correlation with overall survival and progression-free survival among EEC patients. Finally, we tested the ability of ADI1 to induce migration and invasion capabilities in EC cell lines. Altogether, these results suggest that ADI1 could be a potential therapeutic target in poor-prognosis SCs and other Ecs with abnormal p53 expression.This study was funded by the Instituto de Salud Carlos III (ISCIII) through projects PI20/00502, CP19/00025, CB16/12/00231, PI16/00692, PI18/00573, PI21/00672, CP17/00063 and PI18/00795; and by the Spanish Ministry of Science, Innovation and Universities (Ministerio de Ciencia, Innovación y Universidades, RTI2018-099200-BI00), co-funded by the European Regional Development Fund (ERDF) as part of the “A way to make Europe” programme and the European Social Fund (ESF) as part of the “Investing in Your Future” programme. This study was also supported by the “Xarxa de Bancs de Tumors de Catalunya” and sponsored by “Pla Director d’Oncologia de Catalunya (XBTC)”, “IRBLleida Biobank” (B.0000682) and “Plataforma Biobancos” PT20/00021. We also thank the Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR1368 and 2017SGR696) and the “Asociación Española Contra el Cáncer” (AECC; Grupos Estables 2018 and LABAE19004LLOB). M.J. is a Serra Húnter Fellow. N.E. (MS19/00025) and D.L-N. (MS17/00063) are recipients of a Miguel Servet research scheme (co-funded by the ESF program “Investing in Your Future”). C. M-L. holds a predoctoral fellowship from the Generalitat de Catalunya (2020FI_B2 00099) and the predoctoral fellowship “Ajuts 2021 de Promoció de la Recerca en Salut-9a edició” from IRBLleida/Diputació de Lleida. IRBLleida is a CERCA Program/Generalitat of Catalonia

Scientific authorship in the areas of science and technology. International policies and editorial practices in Spanish scholarly journals

La autoría científica está ligada al crédito, al mérito científico y a la ética personal, existiendo evidencias sobre comportamientos inadecuados que plantean mejorar la regulación de las condiciones para otorgar la autoría de un trabajo científico. Esta regulación es competencia de las asociaciones de edición científica y de las propias revistas, por lo que el objetivo de este trabajo es analizar cuál es la situación de las políticas internacionales sobre autoría científica y de las prácticas editoriales de las revistas españolas en las áreas de ciencia y tecnología. Se realizo un análisis de contenido transversal de los manuales de edición científica y de una muestra de 37 revistas españolas de prestigio y se comprobaron los criterios sobre autoría, las responsabilidades derivadas, la función de los agradecimientos, el número de autores, orden de firma y la responsabilidad de correspondencia. Se observa como resultados centrales datos preocupantes: solo el 15% de los manuales aciertan a especificar de forma adecuada los criterios y entre las revistas solo el 8%. Se comparan los datos con estudios similares realizados en las áreas biomédicas. Se discute la incidencia de la no regulación en el comportamiento de los autores así como las implicaciones de la coautoría en los procesos de evaluación de la actividad científica.Scientific authorship is tied to scientific recognition, merit, and personal ethics. There is evidence of inappropriate behaviours associated with several factors that call for a better regulation of the conditions in which authorship of a scientific work is assigned. This regulation falls within the competences of the associations of scientific publishers and the journals themselves. The aim of this paper is to analyse the situation of international policies and editorial practices of Spanish journals in the areas of Science and Technology. A transversal content analysis of the manuals of good practices in academic publishing and a sample of 37 Spanish prestigious journals was carried out, with special attention paid to the criteria for authorship, derived liabilities, the role of acknowledgements, number of authors, author ordering, and responsibilities of the corresponding author. The results give cause for concern: only 15% of the manuals and 8% of the journals manage to declare these criteria properly. We compare these results with those of other areas, such as Biomedicine, where similar studies have been carried out, and we discuss the impact of non-regulation on authors’ behaviour and scientific ethics, as well as the implications of co-authorship in scholarly evaluation procedures

FDG-PET-based neural correlates of Addenbrooke’s cognitive examination III scores in Alzheimer’s disease and frontotemporal degeneration

IntroductionThe Addenbrooke’s Cognitive Examination III (ACE-III) is a brief test useful for neuropsychological assessment. Several studies have validated the test for the diagnosis of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). In this study, we aimed to examine the metabolic correlates associated with the performance of ACE-III in AD and behavioral variant FTD.MethodsWe enrolled 300 participants in a cross-sectional study, including 180 patients with AD, 60 with behavioral FTD (bvFTD), and 60 controls. An 18F-Fluorodeoxyglucose positron emission tomography study was performed in all cases. Correlation between the ACE-III and its domains (attention, memory, fluency, language, and visuospatial) with the brain metabolism was estimated.ResultsThe ACE-III showed distinct neural correlates in bvFTD and AD, effectively capturing the most relevant regions involved in these disorders. Neural correlates differed for each domain, especially in the case of bvFTD. Lower ACE-III scores were associated with more advanced stages in both disorders. The ACE-III exhibited high discrimination between bvFTD vs. HC, and between AD vs. HC. Additionally, it was sensitive to detect hypometabolism in brain regions associated with bvFTD and AD.ConclusionOur study contributes to the knowledge of the brain regions associated with ACE-III, thereby facilitating its interpretation, and highlighting its suitability for screening and monitoring. This study provides further validation of ACE-III in the context of AD and FTD

Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative

The prognostic significance of tumor-infiltrating lymphocytes, PD-L1, BRCA mutation status and tumor mutational burden in early-stage high-grade serous ovarian carcinoma. A study by the Spanish Group for Ovarian Cancer Research (GEICO)

Early stages are under-represented in studies on the molecular and immune features of high-grade serous ovarian carcinoma (HGSOC), and specific studies focused on early-stage HGSOC are required for a better prognostic stratification and to personalize chemotherapy. The aim of this study was to determine the prognostic significance of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs), tumoral cell PD-L1 expression, BRCA mutational status and tumor mutation burden (TMB) in early-stage HGSOC. A retrospective study was performed on stage I and II HGSOC from the Molecular Reclassification of Early Stages of Ovarian Cancer (RECLAMO) cohort from the Spanish Group of Ovarian Cancer Research (GEICO). Centralized histological typing was performed based on morphological and immunohistochemical features. Intraepithelial (i) and stromal (s) CD8+ and CD4+ T cells and PD-L1 were evaluated on tissue microarrays by immunohistochemistry. BRCA1 and BRCA2 mutation status and TMB were analyzed in tumor DNA using next-generation sequencing. The study included 124 tumors. High iCD8+ (>20 TILs/core), low/intermediate CD4+ (35/core) were associated with favorable outcomes. Tumor cell PD-L1 expression (TPS ≥ 1) was present in only 8% of tumors. In total, 11 (16%) and 6 (9%) out of 69 HGSOC tested carried pathogenic or likely pathogenic BRCA1 or BRCA2 mutations, respectively. Median TMB of 40 tumors analyzed was 5.04 mutations/Mb and only 6 tumors had 10 or more mutations/Mb. BRCA status and TMB were not associated with TILs or prognosis. When compared with studies on advanced HGSOC, our results suggested that prognostic variables differed according to stage and that more studies focused on early stages of HGSOC are needed to better stratify these tumors: This work was supported by Instituto de Salud Carlos III (ISCIII) (grants PI19/01331, PI22/01892 and PMP22/00054); CIBERONC (grant CB16/12/00316); European Development Re gional Fund ‘A way to achieve Europe’ (FEDER), Spanish Group of Research in Ovarian Cancer (GEICO group); and by the Spanish Association Against Cancer Scientific Foundation (AECC)