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Background: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. Objective: To relate plasma amyloid-β (Aβ), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aβ, measured using positron emission tomography (PET), examine the accuracy of plasma Aβ to predict brain Aβ positivity, and the relation of APOE ɛ4 with plasma Aβ. Methods: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aβ42/Aβ40 ratio measured with Simoa. Brain Aβ burden was measured as global SUVR with 18F-Florbetaben PET examined continuously and categorically. Results: Plasma Aβ42/Aβ40 ratio was inversely associated with global Aβ SUVR (β= –0.13, 95% Confidence Interval (CI): –0.23, –0.03; p = 0.013) and Aβ positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p

The microbiota-gut-brain axis is a complex interconnected system altered in schizophrenia. The antioxidant N-acetylcysteine (NAC) has been proposed as an adjunctive therapy to antipsychotics in clinical trials, but its role in the microbiota-gut-brain axis has not been sufficiently explored. We aimed to describe the effect of NAC administration during pregnancy on the gut-brain axis in the offspring from the maternal immune stimulation (MIS) animal model of schizophrenia. Pregnant Wistar rats were treated with PolyI:C/Saline. Six groups of animals were studied according to the study factors: phenotype (Saline, MIS) and treatment (no NAC, NAC 7 days, NAC 21 days). Offspring were subjected to the novel object recognition test and were scanned using MRI. Caecum contents were used for metagenomics 16S rRNA sequencing. NAC treatment prevented hippocampal volume reduction and long-term memory deficits in MIS-offspring. In addition, MIS-animals showed lower bacterial richness, which was prevented by NAC. Moreover, NAC7/NAC21 treatments resulted in a reduction of proinflammatory taxons in MIS-animals and an increase in taxa known to produce anti-inflammatory metabolites. Early approaches, like this one, with anti-inflammatory/anti-oxidative compounds, especially in neurodevelopmental disorders with an inflammatory/oxidative basis, may be useful in modulating bacterial microbiota, hippocampal size, as well as hippocampal-based memory impairments.

Substance use disorders are more prevalent in schizophrenia, but the causal links between both conditions remain unclear. Maternal immune activation (MIA) is associated with schizophrenia which may be triggered by stressful experiences during adolescence. Therefore, we used a double-hit rat model, combining MIA and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to Sprague-Dawley dams. Their male offspring underwent five episodes of unpredictable stress every other day from postnatal day 28 to 38. When animals reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, Pavlovian and instrumental conditioning, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration and increased the motivation for the drug; however, PUS reduced cocaine intake, an effect that was reversed in MIA + PUS rats. We found concomitant brain alterations: MIA + PUS altered the structure and function of the dorsal striatum, increasing its volume and interfering with glutamatergic dynamics (PUS decreased the levels of NAA + NAAG but only in LPS animals) and modulated specific genes that could account for the restoration of cocaine intake such as the pentraxin family. On its own, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum, also having a profound effect on the dorsal striatal transcriptome. However, these effects were obliterated when PUS occurred in animals with MIA experience. Our results describe an unprecedented interplay between MIA and stress on neurodevelopment and the susceptibility to cocaine addiction.

Introduction: Prenatal infections are associated with an increased risk of the onset of schizophrenia. Rodent models of maternal immune stimulation (MIS) have been extensively used in preclinical studies. However, many of these studies only include males, omitting pathophysiological features unique to females. The aim of this study is to characterize the MIS model in female rats using positron emission tomography (PET), structural magnetic resonance imaging (MR), and neuroplasticiy studies. Methods: In gestational day 15, Poly I:C (or Saline) was injected into pregnant Wistar rats to induce the MIS model. Imaging studies: [18F]-fluoro-2-deoxy-D-glucose-PET scans of female-offspring were acquired at post-natal day (PND) 35 and PND100. Furthermore, T2-MR brain images were acquired in adulthood. Differences in FDG uptake and morphometry between groups were assessed with SPM12 and Regions of Interest (ROI) analyses. Ex vivo study: The density of parvalbumin expressing interneurons (PV), perineuronal nets (PNN), and parvalbumin expressing interneurons surrounded by perineuronal nets (PV-PNN) were evaluated in the prelimbic cortex and basolateral amygdala using confocal microscopy. ROIs and neuroplasticity data were analyzed by 2-sample T-test and 2-way-ANOVA analyses, respectively. Results: A significant increase in brain metabolism was found in all animals at adulthood compared to adolescence. MIS hardly modified brain glucose metabolism in females, highlighting a significant hypometabolism in the thalamus at adulthood. In addition, MIS induced gray matter (GM) enlargements in the pituitary, hippocampus, substantia nigra, and cingulate cortex, and GM shrinkages in some thalamic nuclei, cerebelar areas, and brainstem. Moreover, MIS induced white matter shrinkages in the cerebellum, brainstem and corpus callosum, along with cerebrospinal fluid enlargements in the lateral and 4th ventricles. Finally, MIS reduced the density of PV, PNN, and PV-PNN in the basolateral amygdala. Conclusion: Our work showed in vivo the differential pattern of functional and morphometric affectation in the MIS model in females, as well as the deficits caused at the synaptic level according to sex. The differences obtained highlight the relevance of including both sexes in psychiatric research in order to consider their pathophysiological particularities and successfully extend the benefits obtained to the entire patient population. MS-M was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (PI17/01766, BA21/0030); co-financed by European Regional Development Fund (ERDF), “A way to make Europe”; project PID2021_128862OB-I00 funded by MCIN/AEI/10.13039/501100011033/FEDER, UE; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM; project number CB07/09/0031); Delegación del Gobierno para el Plan Nacional sobre Drogas (project number 2017/085); and Fundación Alicia Koplowitz. MC-V was supported by Fundación Tatiana Pérez de Guzmán el Bueno as scholarship holder of this institution, and EU Joint Programme—Neurodegenerative Disease Research (JPND). DR-M was supported by Consejería de Educación e Investigación, Comunidad de Madrid, co-funded by European Social Fund “Investing in your future” (grant number PEJD-2018-PRE/BMD-7899). NL-R was supported by Instituto de Investigación Sanitaria Gregorio Marañón, “Programa Intramural de Impulso a la I+D+I 2019”. MD’s work was supported by Ministerio de Ciencia e Innovación (MCIN) and Instituto de Salud Carlos III (PT20/00044). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). JN was supported by the project RTI2018-098269-B-I00 and PID2021-127595OB-I00 financed by the Spanish Ministry of Science and Innovation/AEI/10.13039/501100011033/(“FEDER Una manera de hacer Europa”) and the Generalitat Valenciana (PROMETEU/2020/024).

espanolLa investigacion educativa tiene como proposito conocer detallada y minuciosamente un problema de conocimiento, asi como exponer y publicar los descubrimientos que arroja la indagacion. El cuidado que ponen los investigadores en su trabajo hace posible que el lector cuente con informacion confiable y comprenda como son los actores, las instituciones y las practicas que se desarrollan en los espacios educativos. La docencia y la investigacion aparecen en todas las definiciones que se dan sobre las funciones basicas de la institucion universitaria. La investigacion para la creacion del conocimiento y la docencia para su diseminacion. Estas dos funciones tienen su razon de ser en el aprendizaje de los estudiantes. Del mismo modo se senala que la mision de la universidad es la busqueda, desarrollo y difusion del conocimiento en todos los campos del saber, convirtiendose de este modo en referencia del conocimiento y del desarrollo tecnologico. El presente articulo describe y compara diferentes literaturas sobre Investigacion educativa en la educacion superior y sus beneficios. Para ello, se recolecta esta informacion de diferentes fuentes bibliograficas adquiridas de bases de datos (SCOPUS, PubMed, Biblioteca Cochrane, Google Scholar) valorando la calidad y veracidad de la informacion recopilada, asi como la actualidad del contenido. Sin duda alguna que la investigacion cientifica en cualquier area es beneficiosa no solo para el investigador, institucion u universidad. Tambien lo es para el pais, las investigaciones se realizan por que existen problemas de diferentes indoles, a los cuales hay que buscarles respuestas y soluciones. Sin embargo paras poder investigar hay que tener pautas que hay que cumplir para que dicha investigaciones sea exitosas y son los metodos de investigacion. Pero no hay investigador si no hay un docente que ensene a investigar, es por ello que tambien es de suma importancia formar a buenos docentes, ya que esto es una cadena. De todas maneras el proceso investigativo esta en innovar, que tal vez sea uno de los elementos mas complejos al iniciar una investigacion, es decir, “el que investigar” y que esta investigacion genere los resultados esperados y que puedan ser medibles, comparables y auditables. EnglishThe purpose of educational research is to know in detail and in detail a knowledge problem, as well as to expose and publish the discoveries that the inquiry throws up. The care that researchers put in their work makes it possible for the reader to have reliable information and understand what the actors, institutions and practices that develop in educational spaces are like. Teaching and research appear in all the definitions given about the basic functions of the university institution. Research for the creation of knowledge and teaching for its dissemination. These two functions have their reason for being in student learning. In the same way, it is pointed out that the mission of the university is the search, development and dissemination of knowledge in all fields of knowledge, thus becoming a reference for knowledge and technological development. This article describes and compares different literatures on Educational Research in Higher Education and its benefits. To do this, this information is collected from different bibliographic sources acquired from databases (SCOPUS, PubMed, Cochrane Library, Google Scholar), assessing the quality and veracity of the information collected, as well as the timeliness of the content. Without a doubt, scientific research in any area is beneficial not only for the researcher, institution or university. It is also the case for the country, investigations are carried out because there are problems of different kinds, to which answers and solutions must be sought. However, to be able to investigate, you must have guidelines that must be met for such investigations to be successful and these are the investigation methods. But there is no researcher if there is no teacher who teaches research, that is why it is also very important to train good teachers, since this is a chain. In any case, the investigative process is about innovating, which may be one of the most complex elements when starting an investigation, that is, "the one to investigate" and that this investigation generates the expected results that can be measurable, comparable and auditable.

espanolEl termino hipertension pulmonar (HP) agrupa a un conjunto heterogeneo de enfermedades que tienen en comun una remodelacion obstructiva en el lecho vascular pulmonar. Esta alteracion provoca un estado hemodinamico caracterizado por una elevacion sostenida de la presion en el circuito arterial pulmonar. La morbilidad y mortalidad de esta enfermedad son la consecuencia del fracaso de la compensacion del ventriculo derecho (VD) a este aumento de la poscarga. El presente articulo describe y compara diferentes literaturas sobre la Fisiopatologia de la hipertension pulmonar. Para ello, se recolecta esta informacion de diferentes fuentes bibliograficas adquiridas de bases de datos (SCOPUS, PubMed, Biblioteca Cochrane, Google Scholar) valorando la calidad y veracidad de la informacion recopilada, asi como la actualidad del contenido. La hipertension pulmonar es una enfermedad que puede producir varias complicaciones en el organismo e inclusive puede provocar la muerte. En los ultimos anos se han realizado avances en el aspecto fisiopatologico de la enfermedad, que han logrado que se incorporen mas alternativas terapeuticas para su tratamiento que pueden lograr una mejor calidad de vida y disminucion de las mortalidades asociadas a esta enfermedad. La fisiopatologia de la enfermedad esta asociada a modificaciones vasculares que aumentan la resistencia vascular pulmonar. Estas incluyen: la vasoconstriccion, la proliferacion del musculo liso, la inflamacion, la apoptosis endotelial, la proliferacion endotelial resistente a la apoptosis, la fibrosis, la trombosis in-situ, y finalmente, las lesiones plexiformes. En cuanto al diagnostico es recomendable la ecocardiografia transitoria y cateterismo cardiaco derecho para su confirmacion. El tratamiento de la patologia se basa en el uso de farmacos que se dirigen a las vias de la endotelina, el oxido nitrico o la prostaciclina. Ademas, existen tratamientos con suplementos de oxigeno, diureticos, digoxina y la utilizacion de anticoagulantes EnglishThrough the following research, a critical analysis of the literature on individuals in cultural transitions in higher education is provided, namely, international students in culturally unfamiliar contexts; international student teachers and more culturally diverse classrooms; and local students in increasingly culturally diverse classes. All of these people are actors exposed to new and changing experiences that are expected to impact their motivation and commitment. Two broad perspectives emerging from the literature were used: an adaptive perspective that represents research based on unilateral, bilateral, or reciprocal conceptualizations, and a transformational perspective, which captures experiential learning research that leads to personal and academic development. The analysis highlights how motivation is the fundamental construct for the formation of individuals. This leads to numerous suggestions for future research, including: addressing the neglected role of agency in research on the sociocultural adaptation of international students and the lack of research on successful adaptation processes; examine the confusing problem of socialization in new cultural and educational settings and the level of competence in the instructional environment, which has an impact on participation; and scrutinizing the proposed link between deep-level motivated engagement in cultural transitions and the emergence of transformative experiences. A case is made for research on the commitment and motivation of individuals in cultural transitions to be conceptually and methodologically stronger and broader, moving from studies of individual groups of individuals in need of adaptation.

Background: The National Institute on Aging (NIA)/Alzheimer’s Association (AA) 2018 framework conceptualizes Alzheimer’s disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer’s continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change. Objective: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age. Methods: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15±3.34; 72.0%women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT). Results: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-). Conclusion: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer’s continuum, was related to verbal learning.

The likely involvement of inflammation and oxidative stress (IOS) in mental disease has led to advocate anti-oxidant and anti-inflammatory drugs as therapeutic strategies in the treatment of schizophrenia. Since omega-3 fatty acids (ω-3) show anti-inflammatory/neuroprotective properties, we aim to evaluate whether ω-3 treatment during adolescence in the maternal immune stimulation (MIS) animal model of schizophrenia could prevent the brain and behavioural deficits described in adulthood. At gestational day 15, PolyI:C (4 mg/kg) or saline (VH) were injected to pregnant Wistar rats. Male offspring received ω-3 (800 mg/kg) or saline (Sal) daily from postnatal day (PND) 35-49, defining 4 groups: MIS-ω-3; MIS-Sal; VH-ω-3 and VH-Sal. At PND70, rats were submitted to prepulse inhibition test (PPI). FDG-PET and T2-weighted MRI brain studies were performed in adulthood and analyzed by means of SPM12. IOS markers were measured in selected brain areas. MIS-offspring showed a PPI deficit compared with VH-offspring and ω-3 treatment prevented this deficit. Also, ω-3 reduced the brain metabolism in the deep mesencephalic area and prevented the volumetric abnormalities in the hippocampus but not in the ventricles in MIS-offspring. Besides, ω-3 reduced the expression of iNOS and Keap1 and increased the activity/concentration of HO1, NQO1 and GPX. Our study demonstrates that administration of ω-3 during adolescence prevents PPI behavioural deficits and hippocampal volumetric abnormalities, and partially counteracts IOS deficits via iNOS and Nrf2-ARE pathways in the MIS model. This study highlights the need for novel strategies based on anti-inflammatory/anti-oxidant compounds to alter the disease course in high-risk populations at early stages.

Deep brain stimulation (DBS) is a powerful neurostimulation therapy proposed for the treatment of several neuropsychiatric disorders. However, DBS mechanism of action remains unclear, being its effects on brain dynamics of particular interest. Specifically, DBS reversibility is a major point of debate. Preclinical studies in obesity showed that the stimulation of the lateral hypothalamus (LH) and nucleus accumbens (NAcc), brain centers involved in satiety and reward circuits, are able to modulate the activity of brain structures impaired in this pathology. Nevertheless, the long-term persistence of this modulation after DBS withdrawal was unexplored. Here we examine the in vivo presence of such changes 1 month after LH- and NAcc-DBS, along with differences in synaptic plasticity, following an exploratory approach. Thus, both stimulated and non-stimulated animals with electrodes in the NAcc showed a common pattern of brain metabolism modulation, presumably derived from the electrodes’ presence. In contrast, animals stimulated in the LH showed a relative metabolic invariance, and a reduction of neuroplasticity molecules, evidencing long-lasting neural changes. Our findings suggest that the reversibility or persistence of DBS modulation in the long-term depends on the selected DBS target. Therefore, the DBS footprint would be influenced by the stability achieved in the neural network involved during the stimulation. This research was supported by the Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III (projects PI14/00860 and PI17/01766, and grant CPII14/00005), co-financed by European Regional Development Fund (ERDF), “A way of making Europe”, CIBERSAM, Delegación del Gobierno para el Plan Nacional sobre Drogas (2017/085), Fundación Mapfre and Fundación Alicia Koplowitz. MCV was supported by Fundación Tatiana Pérez de Guzmán el Bueno as scholarship holder of this institution. DRM was supported by Consejería de Educación e Investigación, Comunidad de Madrid, co-funded by European Social Fund “Investing in your future” (grant, PEJD-2018-PRE/BMD- 7899). NLR was supported by Instituto de Investigación Sanitaria Gregorio Marañón, "Programa Intramural de Impulso a la I+D+I 2019”. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV‐2015‐0505). Support for Nacher’s lab came from Ministry of Economy and Competitiveness (SAF2015- 68436-R), Generalitat Valenciana (PROMETEO2013/069) and Fundación Alicia Koplowitz (FAK2012/01).

There is evidence that in schizophrenia, imbalances in inflammatory and oxidative processes occur during pregnancy and in the early postnatal period, generating interest in the potential therapeutic efficacy of anti-inflammatory and antioxidant compounds. Mangiferin is a polyphenolic compound abundant in the leaves of Mangifera indica L. that has robust antioxidant and anti-inflammatory properties, making it a potential candidate for preventive or co-adjuvant therapy in schizophrenia. Hence, this study set-out to evaluate the effect of mango leaf extract (MLE) in a model of schizophrenia based on maternal immune activation, in which Poly I:C (4 mg/kg) is administered intravenously to pregnant rats. Young adult (postnatal day 60-70) or adolescent (postnatal day 35-49) male offspring received MLE (50 mg/kg of mangiferin) daily, and the effects of MLE in adolescence were compared to those of risperidone, assessing behavior, brain magnetic resonance imaging (MRI), and oxidative/inflammatory and antioxidant mediators in the adult offspring. MLE treatment in adulthood reversed the deficit in prepulse inhibition (PPI) but it failed to attenuate the sensitivity to amphetamine and the deficit in novel object recognition (NOR) induced. By contrast, adolescent MLE treatment prevented the sensorimotor gating deficit in the PPI test, producing an effect similar to that of risperidone. This MLE treatment also produced a reduction in grooming behavior, but it had no effect on anxiety or novel object recognition memory. MRI studies revealed that adolescent MLE administration partially counteracted the cortical shrinkage, and cerebellum and ventricle enlargement. In addition, MLE administration in adolescence reduced iNOS mediated inflammatory activation and it promoted the expression of biomarkers of compensatory antioxidant activity in the prefrontal cortex and hippocampus, as witnessed through the reduction of Keap1 and the accumulation of NRF2 and HO1. Together, these findings suggest that MLE might be an alternative therapeutic or preventive add-on strategy to improve the clinical expression of schizophrenia in adulthood, while also modifying the time course of this disease at earlier stages in populations at high-risk. EB, JAG-P and ST-S work was supported by the “Fondo Europeo de Desarrollo Regional” (FEDER)-UE “A way to build Europe” from the “Ministerio de Economía y Competitividad” (RTI2018-099778-B-I00); from the “Plan Nacional sobre Drogas, Ministerio de Sanidad, Consumo y Bienestar Social” (2019I041); from the “Ministerio de Salud-Instituto de Salud Carlos III” (PI18/01691); from the “Programa Operativo de Andalucía FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejería Salud y Familias, Junta de Andalucía” (PI-0080- 2017, PI-0009-2017), “Consejería de Salud y Familias, Junta de Andalucía” (PI-0134-2018 and PEMP-0008-2020); from the “Consejería de Transformación Económica, Industria, Conocimiento y Universidad, Junta de Andalucía” (P20_00958 and CTS-510); from the CEIMAR (CEIJ-003); from the “Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz-INiBICA” (LI19/06IN-CO22; IN-C09); from the “CIBERSAM”: CIBER-Consorcio Centro de Investigación Biomédica en Red- (CB07/09/0033), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 955684. CM, LC and MTF-P were supported by the Spanish Ministry of Science and Technology (PID2020- 116229RB-I00) and European Regional Development Fund (ERDF). KM and JCL were supported by the “MICINN” (PID2019-109033RB-I00) and the “CIBERSAM”: CIBERConsorcio Centro de Investigación Biomédica en Red- (CB07/ 09/0026), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación. MLS-M was supported by the “Ministerio de Ciencia, Innovación, Instituto de Salud Carlos III” (PI17/ 01766, BA21/00030), co-financed by European Regional Development Fund (ERDF), “A way to make Europe”; from the “CIBERSAM”: CIBERConsorcio Centro de Investigación Biomédica en Red- (CB07/09/0031), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación; from the “Delegación del Gobierno para el Plan Nacional sobre Drogas” (2017/085); from the “Fundación Mapfre” and “Fundación Alicia Koplowitz.” MD work was supported by the “Ministerio de Ciencia e In review 18/ 28 Innovación” (MCIN) and “Instituto de Salud Carlos III” (ISCIII) (PT20/00044); from the “CIBERSAM” CIBERConsorcio Centro de Investigación Biomédica en Red-(CB07/ 09/0031). The CNIC is supported by the ISCIII, the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí

BACKGROUND AND PURPOSE Minocycline is a broad-spectrum antibiotic, effective as a chronic treatment for recurrent bacterial infections. Beyond its antibiotic action, minocycline also has important anti-inflammatory, antioxidant and antiapoptotic properties. Its efficacy has therefore been evaluated in many neurodegenerative and psychiatric diseases that have an inflammatory basis. Our aim was to review preclinical and clinical studies performed in neurological and psychiatric diseases whose treatment involved the use of minocycline and thereby to discern the possible beneficial effect of minocycline in these disorders. METHODS Completed and ongoing preclinical studies and clinical trials of minocycline for both neurodegenerative diseases and psychiatric disorders, published from January 1995 to January 2020, were identified through searching relevant databases (https://www.ncbi.nlm.nih.gov/pubmed/, https://clinicaltrials.gov/). A total of 74 preclinical studies and 44 clinical trials and open-label studies were selected. RESULTS The results of the nearly 20 years of research identified are diverse. While minocycline mostly proved to be effective in animal models, clinical results showed divergent outcomes, with positive results in some studies counterbalanced by a number of cases with no significant improvements. Specific data for each disease are further individually described in this review. CONCLUSIONS Despite minocycline demonstrating antioxidant and anti-inflammatory effects, discrepancies between preclinical and clinical data indicate that we should be cautious in analyzing the outcomes. Improving and standardizing protocols and refining animal models could help us to determine if minocycline really is a useful drug in the treatment of these pathologies.

Deep brain stimulation (DBS) is an invasive neurosurgical technique based on the application of electrical pulses to brain structures involved in the patient's pathophysiology. Despite the long history of DBS, its mechanism of action and appropriate protocols remain unclear, highlighting the need for research aiming to solve these enigmas. In this sense, evaluating the in vivo effects of DBS using functional imaging techniques represents a powerful strategy to determine the impact of stimulation on brain dynamics. Here, an experimental protocol for preclinical models (Wistar rats), combined with a longitudinal study [

Vulnerability to addiction may be given by the individual's risk of developing an addiction during their lifetime. A challenge in the neurobiology of drug addiction is understanding why some people become addicted to drugs. Here, we used positron emission tomography (PET) and statistical parametric mapping (SPM) to evaluate changes in brain glucose metabolism in response to chronic morphine self-administration (MSA) in two rat strains with different vulnerability to drug abuse, Lewis (LEW) and Fischer 344 (F344). Four groups of animals were trained to self-administer morphine or saline for 15 days. 2-deoxy-2-[18F]-fluoro-D-glucose (FDG)-PET studies were performed on the last day of MSA (acquisition phase) and after 15 days of withdrawal. PET data were analyzed using SPM12. LEW-animals self-administered more morphine injections per session than F344-animals. We found significant brain metabolic differences between LEW and F344 strains in the cortex, hypothalamus, brainstem, and cerebellum. In addition, the different brain metabolic patterns observed after the MSA study between these rat strains indicate differences in the efficiency of neural substrates to translate the drug effects, which could explain the differences in predisposition to morphine abuse between one individual and another. These findings have important implications for the use of these rat strains in translational morphine and opiate research. MLS was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (projects PI17/01766, and grant BA21/00030), co-funded by the European Regional Development Fund (ERDF), “A way to make Europe”, CIBERSAM, Delegación del Gobierno para el Plan Nacional sobre Drogas (2017/085), Fundación Mapfre, and Fundación Alicia Koplowitz. EA was supported by grants from Ministerio de Sanidad, Servicios Sociales e Igualdad and Red de Trastornos Adictivos del Instituto de Salud Carlos III (RTA-RD16/020/0022), Delegación del Gobierno para el Plan Nacional sobre Drogas (2016I073), Ministerio de Ciencia e Innovación (PSI2016-80541-P), UNED (Plan de Promoción de la Investigación 2018–2020), and the European Union´s Justice Programme – Drugs Policy Initiatives (JUST-2017-AG-DRUGS- 806996-JUSTSO). NLR was supported by Instituto de Investigación Sanitaria Gregorio Marañón, "Programa Intramural de Impulso a la I + D + I 2019″. MD work was supported by Ministerio de Ciencia e Innovación (MCIN) and Insituto de Salud Carlos III (ISCIII) (PT20/00044). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN), and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV‐2015‐0505). Sí

Background: Heightened levels of inflammation and oxidative stress are thought to be involved in the pathophysiology of schizophrenia. We aimed to assess whether intake of anti-inflammatory and anti-oxidant drugs during pregnancy prevents later schizophrenia-related outcomes in a neurodevelopmental rat model of this disorder. Methods: Pregnant Wistar rats were injected with polyriboinosinic–polyribocytidilic acid (Poly I:C) or saline and subsequently treated with either N-acetyl cysteine (NAC) or omega-3 polyunsaturated fatty acids (PUFAs) until delivery. Controls rats received no treatment. In the offspring, neuroinflammation and anti-oxidant enzyme activity were assessed on postnatal day (PND) 21, 33, 48, and 90. Behavioral testing was performed at PND 90, followed by post-mortem neurochemical assessment and ex vivo MRI. Results: The supplement treatment led to a quicker restoration of the wellbeing of dams. In the adolescent Poly I:C offspring, the supplement treatment prevented an increase in microglial activity and partially prevented a deregulation in the anti-oxidant defense system. In the adult Poly I:C offspring, supplement treatment partially prevented dopamine deficits, which was paralleled by some changes in behavior. Exposure to omega-3 PUFAs prevented the enlargement of lateral ventricles. Conclusion: Intake of over-the-counter supplements may assist in especially targeting the inflammatory response related to schizophrenia pathophysiology, aiding in diminishing later disease severity in the offspring.

This article belongs to the Special Issue Dietary Antioxidants against Neurodegenerative Diseases. Curcumin is a polyphenol extracted from the rhizome of the turmeric plant. Beyond its common use as a culinary spice in Eastern Asia, curcumin has been proposed as a therapeutic compound due to its antioxidant, anti-inflammatory and neuroprotective properties. Thus, its efficacy has been evaluated in various inflammatory-based psychiatric disorders, such as schizophrenia, depression, or autism. Our aim is to review those preclinical and clinical studies carried out in psychiatric disorders whose therapeutic approach has involved the use of curcumin and, therefore, to discern the possible positive effect of curcumin in these disorders. Preclinical studies and completed clinical trials of curcumin for psychiatric disorders published from January 2005 to October 2021 were identified through searching relevant databases until 31st October 2021. Sixty-five preclinical studies and 15 clinical trials and open-label studies were selected. Results showed a bias toward studies in depression and, to a lesser extent, schizophrenia. In all disorders, the results were positive in reducing psychiatric deficits. Despite the considerable number of beneficial outcomes reported, the small number of trials and the heterogeneity of protocols make it difficult to draw solid conclusions about the real potency of curcumin in psychiatric disorders. M.L.S.-M. was supported by the Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III (project number PI17/01766, and grant number BA21/00030), co-financed by the European Regional Development Fund (ERDF), "A way to make Europe", CIBER de Salud Mental (project number CB07/09/0031), Delegación del Gobierno para el Plan Nacional sobre Drogas (project number 2017/085); and Fundación Alicia Koplowitz (FAK16/01). D.R.-M. was supported by Consejería de Educación e investigación, Comunidad de Madrid, co-funded by the European Social Fund "Investing in your future" (grant, PEJD-2018-PRE/BMD-7899). N.L.-R. was supported by the Instituto de investigación Sanitaria Gregorio Marañón, "Programa Intramural de Impulso a la I+D+I 2019". The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).

In this paper, we propose a novel Machine Learning Model based on Bayesian Linear Regression intended to deal with the low sample-to-variable ratio typically found in neuroimaging studies and focusing on mental disorders. The proposed model combines feature selection capabilities with a formulation in the dual space which, in turn, enables efficient work with neuroimaging data. Thus, we have tested the proposed algorithm with real MRI data from an animal model of schizophrenia. The results show that our proposal efficiently predicts the diagnosis and, at the same time, detects regions which clearly match brain areas well-known to be related to schizophrenia. This paper is part of the project PID2020-115363RB-I00 funded by MCIN/AEI/10.13039/ 501100011033. A.B.-L.’s work is funded by the Community of Madrid through the “Excellence of University Teaching Staff” line of the Multi-year Agreement with UC3M (EPUC3M27), within the framework of the V PRICIT. M.L.S.-M.’s was supported by Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III (project number PI17/01766, and grant number BA21/00030), co-financed by European Regional Development Fund (ERDF), “A way to make Europe”, CIBER de Salud Mental (project number CB07/09/0031), Delegación del Gobierno para el Plan Nacional sobre Drogas (project number 2017/085); Fundación Mapfre and Fundación Alicia Koplowitz. M.D.’s work was supported by Ministerio de Ciencia e Innovación (MCIN) and Instituto de Salud Carlos III (ISCIII) (PT20/00044). The CNIC is supported by the ISCIII, the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).

Substance use disorders are more prevalent in schizophrenia, worsening its course and prognosis. Here, we used a double-hit rat model, combining maternal immune activation (MIA) and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to 5 episodes of unpredictable stress every other day during adolescence (from postnatal day 28 to 38). When rats reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, conditioning processes and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration while PUS reduced cocaine intake, an effect that was reversed by MIA. MIA increased motivation for cocaine and reversed the effects of PUS during extended access. Incubation of seeking was unaffected. Neither hit alone nor their combination impacted Pavlovian or instrumental conditioning or impulsiveness. At the brain level, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum. MIA+PUS altered the structure and function of the dorsal striatum increasing its volume and interfering with glutamatergic dynamics. MIA did not affect the gene expression of the nucleus accumbens but, when combined with PUS, modulated specific genes that could account for the restored cocaine intake. PUS had a profound effect on the dorsal striatal transcriptome however, this was obliterated when PUS occurred in animals with MIA. These results describe a complex interplay between MIA and stress on neurodevelopment and in the susceptibility to develop cocaine addiction.

Background: Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model. Methods: On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue. Results: MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen). Conclusions: MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains., M.L.S. was supported by the Ministerio de Ciencia, Innovacion y Universidades, Instituto de Salud Carlos III (projects PI14/00860 and PI17/01766, and grant CPII14/00005), co-financed by European Regional Development Fund (ERDF), "A way of making Europe", CIBER of Mental Health (CIBERSAM), Delegacion del Gobierno para el Plan Nacional sobre Drogas (2017/085), Fundacion Mapfre and Fundacion Alicia Koplowitz. M.C.-V. was supported by Fundacion Tatiana Perez de Guzman el Bueno. D.R.-M. was supported by Consejeria de Educacion e Investigacion, Comunidad de Madrid, co-funded by European Social Fund "Investing in your future" (grant, PEJD-2018-PRE/BMD-7899). N.L.-R. was supported by Instituto de investigacion Sanitaria Gregorio Maranon. A.R.-M. was supported by Consejeria de Educacion e Investigacion, Comunidad de Madrid, co-funded by European Social Fund "Investing in your future" (grant, PEJ15/BIO/TL-0216). The CNIC was supported by the Spanish Ministerio de Ciencia, Innovacion y Universidades (MCIU) and the Pro-CNIC Foundation. J.C.L. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECOEU-FEDER) SAF2016-75500-R and CIBERSAM. E.B.D., S.T.-S., and J.A.G.-P. were supported by grants: co-financed by the "Fondo Europeo de Desarrollo Regional" (FEDER)-UE "A way to build Europe" from the "Ministerio de Economia y Competitividad" (MINECO: RTI2018-099778-B-I00) and the "Ministerio de SaludInstituto de Salud Carlos III (PI18/01691); from the "Plan Nacional sobre Drogas, Ministerio de Sanidad, Consumo y Bienestar Social" (2019I041); from the "Programa Operativo de Andalucia FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejeria Salud, Junta de Andalucia" (PI-0080-2017 and PI-0009-2017); from the Consejeria de Salud de la Junta de Andalucia (PI-0134-2018); from the University of Cadiz (PR2019-046); from the "Instituto de Investigacion e Innovacion en Ciencias Biomedicas de Cadiz-INiBICA" (IN-C22; LI19/06IN-CO22); from the "Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia" (CTS-510); from the "CIBERSAM" (CB/07/09/0033).

Inflammation and oxidative stress (IOS) are considered key pathophysiological elements in the development of mental disorders. Recent studies demonstrated that the antipsychotic risperidone elicits an antiinflammatory effect in the brain. We administered risperidone for 2-weeks at adolescence to assess its role in preventing brain-related IOS changes in the maternal immune stimulation (MIS) model at adulthood. We also investigated the development of volumetric and neurotrophic abnormalities in areas related to the HPA-axis. Poly I:C (MIS) or saline (Sal) were injected into pregnant Wistar rats on GD15. Male offspring received risperidone or vehicle daily from PND35-PND49. We studied 4 groups (8-15 animals/group): Sal-vehicle, MIS-vehicle, Sal-risperidone and MIS-risperidone. [18F]FDG-PET and MRI studies were performed at adulthood and analyzed using SPM12 software. IOS and neurotrophic markers were measured using WB and ELISA assays in brain tissue. Risperidone elicited a protective function of schizophrenia-related IOS deficits. In particular, risperidone elicited the following effects: reduced volume in the ventricles and the pituitary gland; reduced glucose metabolism in the cerebellum, periaqueductal gray matter, and parietal cortex; higher FDG uptake in the cingulate cortex, hippocampus, thalamus, and brainstem; reduced NFκB activity and iNOS expression; and increased enzymatic activity of CAT and SOD in some brain areas. Our study suggests that some schizophrenia-related IOS changes can be prevented in the MIS model. It also stresses the need to search for novel strategies based on anti-inflammatory compounds in risk populations at early stages in order to alter the course of the disease.

Relatively little is known about the influence of sex and the circadian rhythm on gastrointestinal transit. However, these factors could have an important impact on aspects such as digestion, oral absorption of drugs or the clinical manifestation of gastrointestinal diseases, among others. Remarkably, preclinical models have scarcely taken these factors into consideration. In this study, we assessed the gastrointestinal transit of young adult Wistar Han rats of both sexes, under normal and inverted light cycle. To do this, serial radiographs were taken for 24 h (T0–T24) after intragastric barium administration and subsequently analysed to construct transit curves for each gastrointestinal region. Under a normal light cycle, transit curves were similar, except for a slower transit in females compared with males from T8 to T24. Under the inverted cycle, there was a significant acceleration in stomach emptying (similar in both sexes), emptying of the small intestine (even faster in females) and filling of the caecum and colon (which was also even faster in females). This study confirms, using X-ray non-invasive methods for the first time, that both sex and circadian rhythm (probably through its effect on behaviour) influence gastrointestinal transit in laboratory animals.

Cannabis is widely consumed by adolescents, and is also a potential prior step leading to the use of other drugs later in life (Gateway Hypothesis); however, the evidence for this hypothesis is controversial. This work aimed to increase our understanding of the long-term consequences of adolescent exposure to Δ9-tetrahydrocannabinol (THC) and to test the Gateway Hypothesis, experimentally. We exposed rats of both sexes to THC and studied its effects on reward-related processes, brain morphology (MRI), metabolism (1H-MRS), function (PET) and the transcriptomic profiles of the nucleus accumbens (RNASeq). Lastly, we studied cocaine-induced cellular activation (c-Fos) and cocaine addiction-like behaviours. THC exposure increased Pavlovian to instrumental transfer in males, goal-tracking (regardless of the sex) and impulsivity, but did not affect habit formation. Adolescent THC reduced striatal volume (in females), commissural integrity and ventricular volume. Also, there were lower levels of choline compounds in the cortex of THC-exposed rats and cerebellar hypoactivation in THC-females. THC also modified some of the gene expression programs of the nucleus accumbens, which could contribute to the behavioural features observed. Lastly, THC exposure increased cocaine-induced c-Fos levels in cortical and hypothalamic areas and increased the motivation for cocaine, followed by a higher rebound of use in THC-females after reestablishing low-effort conditions. Critically, acquisition of cocaine self-administration, compulsive seeking, intake under extended access or the incubation of seeking were unaltered. These results suggest that adolescent THC exposure alters psychological and brain development and that the Gateway Hypothesis does not entirely pass the test of preclinical enquiry.

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.

Metabolic syndrome (MetS) is associated with dementia, but it is unclear whether MetS is related to Alzheimer's disease (AD). We investigated the association of MetS with brain amyloid, a key AD feature, and neurodegeneration. A community-based sample of 350 middle-aged Hispanics in New York City had cerebral amyloid β (Aβ) burden ascertained with 18F-Florbetaben positron emission tomography. Neurodegeneration was ascertained as cortical thickness in AD signature regions from 3T brain MRI. MetS and its components (glucose, blood pressure, triglycerides, high-density lipoprotein, adiposity) were defined using the National Institutes of Health criteria. Neither the presence of MetS nor the MetS score was associated with Aβ or neurodegeneration. Among the MetS components, elevated glucose was associated with lower Aβ burden, and this association was not explained by diabetes treatment. Glucose and triglycerides were related to smaller cortical thickness. Our findings suggest that MetS as an arbitrary measure of aggregate metabolic and vascular risk does not capture the risk of AD neuropathology in late middle age and that other approaches to measure the aggregate risk should be examined.

BACKGROUND: Females may have a higher risk of dementia than males. It is not clear if sex differences in Alzheimer’s disease (AD) neuropathology explain the higher risk of dementia in females. Sex differences in AD neuropathology might begin in middle age, decades before the sex differences in dementia are apparent. OBJECTIVE: To examine sex differences in in-vivo AD neuropathology in late middle age. METHODS: We conducted a cross-sectional comparison of AD biomarkers among 266 Hispanic males and females (mean age: 64.0; 71.8% females) without dementia. Amyloid burden was measured as global standardized uptake value ratio (SUVR) with (18)F-Florbetaben Positron Emission Tomography (PET). Neurodegeneration was ascertained as cortical thickness in AD signature areas using brain magnetic resonance imaging. Tau burden was measured as tau SUVR in the middle/inferior temporal gyri and medial temporal cortex with (18)F-MK-6240 in 75 of the 266 participants. RESULTS: Females had higher amyloid SUVR and tau SUVR in the middle/inferior temporal gyri than males. However, females had higher cortical thickness than males and performed better in a test of verbal memory despite having higher AD neuropathology burden. CONCLUSION: Higher amyloid and tau in females compared to males in late middle-age may explain the reported higher dementia risk in elderly females compared to males. Longitudinal follow-up is necessary to examine whether higher amyloid and tau burden in late middle age is followed by increased neurodegeneration and cognitive decline in females as compared with males.

Background An initial antidepressant effect when using deep brain stimulation (DBS) of the subcallosal area of the cingulate cortex (Cg25) to treat resistant depression that could be the result of electrode insertion has been described. We previously showed that electrode insertion into the infralimbic cortex (ILC; the Cg25 rodent correlate) provokes a temporally limited antidepressant-like effect that is counteracted by non-steroidal anti-inflammatory drugs, such as those routinely used for pain relief. Objective We characterized the effect of electrode insertion using functional neuroimaging and evaluated the impact of different analgesics on this effect. Methods The effect of electrode insertion into the ILC was evaluated by positron emission tomography. The effect of analgesics (ibuprofen, tramadol and morphine) on the behavioral effect induced by electrode insertion were evaluated through the forced swimming test and the novelty suppressed feeding test. Furthermore, glial fibrillary acidic protein (GFAP) and p11 expression were measured. Results Electrode implantation produces an antidepressant- and anxiolytic-like effect, a local decrease in glucose metabolism, and changes in several brain regions commonly related to depression and the antidepressant response. Ibuprofen counteracted the behavioral and molecular changes produced by electrode insertion (changes in GFAP and p11 protein expression). However, analgesics with no anti-inflammatory properties (e.g., tramadol) neither counteract the behavioral effects of electrode implantation nor the molecular mechanisms triggered. Conclusions Analgesics without anti-inflammatory properties may not limit the transient benefit produced by electrode insertion reducing the time required to achieve remission in depressive DBS patients.

Las Tecnologías de la Información y la Comunicación (TIC) han experimentado un crecimiento abrumador a partir de la declaratoria de pandemia y el cierre forzado de las instituciones de educación en el mundo. El presente artículo se interesa en la problemática de las TIC respecto a la educación en América Latina, centrándose en la desigualdad de género, el nivel de capacitación de los docentes, así como el acceso a internet; para este propósito se empleó un enfoque metodológico de carácter cualitativo no experimental dado que se realizó un análisis empírico (inductivo). Se encontró que la brecha digital de género todavía es un factor recurrente, que limita y condiciona no solo la educación sino el futuro laboral de las mujeres, también se pudo destacar que la capacitación de los docentes todavía necesita abordarse desde otras perspectivas dado el carácter exógeno de las TIC en la educación. Finalmente se evidencia la dificultad del acceso a internet en la región, y que invita a pensar en estrategias que permitan superar estas desigualdades y problemáticas.

La incorporación de la Responsabilidad Social Corporativa (RSC) en Ecuador, es un tema de reciente interés. En esta problemática se embarca el sistema financiero ecuatoriano que busca orientar sus actividades considerando las expectativas de los diferentes grupos de interés afectados por sus acciones para contribuir al desarrollo sostenible. El objetivo de este documento es realizar un análisis comparativo de la responsabilidad social corporativa de las instituciones financieras (IF) del Ecuador. Por esta razón se toma de referencia tres de las cuatro IF consideradas como grandes, al ser estas las que aplican las normas de responsabilidad social de Global Reporting Initiative (GRI 4) e ISO26000. Sus memorias permitieron la aplicación de un instrumento de medición. Para la categoría de economía se realizó la comparación de sus balances donde destaca la IF que generó mayor rentabilidad a sus inversionistas. En la categoría social, se mide la percepción de sus colaboradores y destaca aquella institución donde estos perciben un mejor ambiente laboral. Y, por último, en la categoría medio ambiente se analizó los datos de las memorias de las tres instituciones y por medio de un check list basado en las GRI 4 se determinó la institución que más cumple con los índices de RSC., The incorporation of Corporate Social Responsibility (CSR) in Ecuador is a topic of recent interest. The Ecuadorian financial system embarks on this problem, which seeks to guide its activities considering the expectations of different interest groups affected by its actions to contribute to sustainable development. The objective of this document is to carry out a comparative analysis of the corporate social responsibility of financial institutions in Ecuador. For this reason, three of the four FIs considered as large are taken as a reference, as these are the ones that apply the Global Reporting Initiative and ISO26000 social responsibility standards. His memories of social responsibility allowed the application of a measuring instrument. For the economy category, a comparison of their balance sheets was made, highlighting the FI that generated the highest profitability for its investors. In the social category, the perception of their collaborators is measured and the institution where they perceive a better work environment stands out. And finally, in the environment category, the data from the reports of the three institutions were analyzed, and by means of a checklist based on the Global Reporting Initiative, the institution that most complies with the CSR indices was determined., A incorporação da Responsabilidade Social Corporativa (RSC) no Equador é um tema de interesse recente. O sistema financeiro equatoriano está embarcando nesta questão, procurando orientar suas atividades considerando as expectativas das diferentes partes interessadas afetadas por suas ações, a fim de contribuir para o desenvolvimento sustentável. O objetivo deste documento é realizar uma análise comparativa da responsabilidade social corporativa das instituições financeiras (IFs) no Equador. Por esta razão, três dos quatro IFs considerados grandes são tomados como referência, pois são eles que aplicam as normas de responsabilidade social da Global Reporting Initiative (GRI 4) e da ISO 26000. Seus relatórios permitiram a aplicação de um instrumento de medição. Para a categoria econômica, foi realizada uma comparação de seus balanços, destacando a FI que gerou a maior rentabilidade para seus investidores. Na categoria social, a percepção de seus funcionários é medida e a instituição onde eles percebem um melhor ambiente de trabalho se destaca. Finalmente, na categoria ambiental, os dados dos relatórios das três instituições foram analisados e uma lista de verificação baseada no GRI 4 foi utilizada para determinar a instituição que mais cumpre com os índices de RSE.

The adsorption of phenolic compounds from wine vinasses onto non ionic resins was investigated with the goal of recovering antioxidant components from the effluent. Batch studies showed that the kinetic data fit to a pseudo-second order kinetic model. Dynamic adsorption studies with macroporous resins packed columns were also conducted to analyze the effect of initial phenolic concentration, the elution speed and the length of the packed bed on breakthrough curves. The experimental data showed that with increased column bed depth from 10 to 20 cm, breakpoint time (tb) increased from 19.6 to 25.6 min. The breakthrough curve was simulated well by Bohart-Adams, Yoon-Nelson and Thomas models. Bohart-Adams model was the only effective to fit the initial part (1–t1/2). The maximum removal capacity (qTh) calculated by Thomas model reached 98.3 mg/g at a flow rate of 5 mL/min.

Alzheimer's disease (AD) is a progressive and debilitating degenerative disorder for which there are currently no effective therapeutic options. Non-invasive neuromodulation, including transcranial direct current stimulation (tDCS), has been investigated for the treatment of cognitive symptoms in AD. Results from clinical and preclinical studies, however, have been somewhat controversial. We investigate whether tDCS delivered to triple transgenic (3xTg) AD mice improves memory deficits and mitigates the development of AD-type neuropathology. 3xTg AD mice and controls were implanted with paddle electrodes over the skull. The cathode was anterior to bregma and the anode anterior to lamda. tDCS was delivered for 20 min/day, 5 days/week over three weeks at 50 μA. Though this amplitude was lower than the one used in the preclinical literature, it generated a high current density compared to the clinical scenario. Memory testing was conducted during treatment weeks 2 and 3. Post-mortem pathological AD markers were studied. Our results show that performance of 3xTg mice in the novel object recognition and Morris water maze tests was significantly impaired compared to that of controls. In addition, AD transgenics had an increased expression of tau, phosphorylated-tau and amyloid precursor protein in the hippocampus. tDCS did not improve behavioural deficits or mitigated the development of AD neuropathology in 3xTg animals. In summary, we found that tDCS at the settings selected in our study was largely ineffective in improving memory performance or altering the expression of AD pathological hallmarks in a validated mouse model.

Purpose The nucleus accumbens (NAcc) has been suggested as a possible target for deep brain stimulation (DBS) in the treatment of obesity. Our hypothesis was that NAcc-DBS would modulate brain regions related to reward and food intake regulation, consequently reducing the food intake and, finally, the weight gain. Therefore, we examined changes in brain glucose metabolism, weight gain and food intake after NAcc-DBS in a rat model of obesity. Procedures Electrodes were bilaterally implanted in 2 groups of obese Zucker rats targeting the NAcc. One group received stimulation one hour daily during 15 days, while the other remained as control. Weight and daily consumption of food and water were everyday registered the days of stimulation, and twice per week during the following month. Positron emission tomography (PET) studies with 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) were performed 1 day after the end of DBS. PET data was assessed by statistical parametric mapping (SPM12) software and region of interest (ROI) analyses. Results NAcc-DBS lead to increased metabolism in the cingulate-retrosplenial-parietal association cortices, and decreased metabolism in the NAcc, thalamic and pretectal nuclei. Furthermore, ROIs analyses confirmed these results by showing a significant striatal and thalamic hypometabolism, and a cortical hypermetabolic region. However, NAcc-DBS did not induce a decrease in either weight gain or food intake. Conclusions NAcc-DBS led to changes in the metabolism of regions associated with cognitive and reward systems, whose impairment has been described in obesity. This research was supported by the Ministry of Economy and Competitiveness ISCIII grants (PI14/00860, CPII14/00005), Ministry of Economy, Industry and Competitiveness (PI17/01766), cofunded by ERDF (FEDER) Funds from the European Commission ``A way of making Europe´´, Fundacion Mapfre, Fundacion Alicia Koplowitz (FAK2016/01), `Delegacion de Gobierno para el Plan Nacional sobre Drogas' (PNSD 2017/085), Comunidad de Madrid (BRADE-CM S2013/ICE-2958) and Fundacion Tatiana Perez de Guzman el Bueno. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

The consumer demand for natural ingredients in cosmetic products is increasing. Phenolic compounds are among the most studied natural antioxidant compounds, they also present antimicrobial, anti-inflammatory or antiaging actions and can permeate through the skin barrier. Grapes contain valuable phenolic components and grape byproducts are widely available low cost raw materials. This review presents an overview of the application of phenolic compounds from grape products and byproducts as sources of natural ingredients for cosmetics.

Image quality of positron emission tomography (PET) tracers that emits high-energy positrons, such as Ga-68, Rb-82, or I-124, is significantly affected by positron range (PR) effects. PR effects are especially important in small animal PET studies, since they can limit spatial resolution and quantitative accuracy of the images. Since generators accessibility has made Ga-68 tracers wide available, the aim of this study is to show how the quantitative results of [Eighteen scans in 12 mice were evaluated, with three different models of tumors: PC12, AR42J, and meningiomas. In addition, three different [All TLR values in the PRC images were significantly different (p 0.05) than the ones from non-PRC images. The relative differences of the tumor TLR values, respect to the case with no PRC, were ΔTLRThe PRC methods proposed provide a significant quantitative improvement in [

The objective of this study was to evaluate the potential use of some vegetal raw materials in personal-care products. Four ethanolic extracts (grape pomace, Pinus pinaster wood chips, Acacia dealbata flowers, and Lentinus edodes) were prepared and total phenolics, monomeric sugars, and antioxidant capacity were determined on alcoholic extracts. Six of the most important groups of cosmetics products (hand cream, body oil, shampoo, clay mask, body exfoliating cream, and skin cleanser) were formulated. Participants evaluated some sensory attributes and overall acceptance by a 10-point scale; the results showed differences among age-intervals, but not between males and females. The results confirmed that all extracts presented characteristics appropriate for their use in cosmetic formulations and their good acceptability by consumers into all cosmetic products. Texture/appearance, spreadability, and skin feeling are important attributes among consumer expectations, but odor and color were the primary drivers and helped differentiate the natural extracts added into all personal-care products.

Image quality of positron emission tomography (PET) tracers that emits high-energy positrons, such as Ga-68, Rb-82, or I-124, is significantly affected by positron range (PR) effects. PR effects are especially important in small animal PET studies, since they can limit spatial resolution and quantitative accuracy of the images. Since generators accessibility has made Ga-68 tracers wide available, the aim of this study is to show how the quantitative results of [Ga-68]DOTA-labeled PET/X-ray computed tomography (CT) imaging of neuroendocrine tumors in mice can be improved using positron range correction (PRC). Eighteen scans in 12 mice were evaluated, with three different models of tumors: PC12, AR42J, and meningiomas. In addition, three different [Ga-68]DOTA-labeled radiotracers were used to evaluate the PRC with different tracer distributions: [Ga-68]DOTANOC, [Ga-68]DOTATOC, and [Ga-68]DOTATATE. Two PRC methods were evaluated: a tissue-dependent (TD-PRC) and a tissue-dependent spatially-variant correction (TDSV-PRC). Taking a region in the liver as reference, the tissue-to-liver ratio values for tumor tissue (TLRtumor), lung (TLRlung), and necrotic areas within the tumors (TLRnecrotic) and their respective relative variations (Delta TLR) were evaluated. All TLR values in the PRC images were significantly different (p < 0.05) than the ones from non-PRC images. The relative differences of the tumor TLR values, respect to the case with no PRC, were Delta TLRtumor 87 +/- 41 \% (TD-PRC) and 85 +/- 46 \% (TDSV-PRC). TLRlung decreased when applying PRC, being this effect more remarkable for the TDSV-PRC method, with relative differences respect to no PRC: Delta TLRlung = - 45 +/- 24 (TD-PRC), - 55 +/- 18 (TDSV-PRC). TLRnecrotic values also decreased when using PRC, with more noticeable differences for TD-PRC: Delta TLRnecrotic = - 52 +/- 6 (TD-PRC), - 48 +/- 8 (TDSV-PRC). The PRC methods proposed provide a significant quantitative improvement in [Ga-68]DOTA-labeled PET/CT imaging of mice with neuroendocrine tumors, hence demonstrating that these techniques could also ameliorate the deleterious effect of the positron range in clinical PET imaging. This work was partially funded by the projects RTC-2015-3772-1, TEC2014-56600-R, and TEC2016-78052-R from the Spanish Ministry of Science and Innovation, Spanish Government, Spanish Ministry of Economy and Competitiveness grants (FIS PI11/00616, FIS PI14/00860, CP08/00017, and CPII14/00005) co-financed by European Regional Development Fund (ERDF), Alicia Koplowitz Foundation and TOPUS S2013/MIT-3024 project from the regional government of Madrid. The research leading to these results has received funding from the Innovative Medicines Initiative (www.imi.europa.eu) Joint Undertaking under grant agreement no 115337, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. Part of the calculations were performed in the ``Cluster de Calculo de Alta Capacidad para Tecnicas Fisicas´´ funded by UCM and by UE under the FEDER programme. Sí

Deep brain stimulation (DBS) is a neurosurgery technique widely used in movement disorders, although its mechanism of action remains unclear. In fact, apart from the stimulation itself, the mechanical insertion of the electrode may play a crucial role. Here we aimed to distinguish between the insertional and the DBS effects on brain glucose metabolism. To this end, electrodes were implanted targeting the medial prefrontal cortex in five adult male Wistar rats. Positron Emission Tomography (PET) studies were performed before surgery (D0) and seven (D7) and nine days (D9) after that. DBS was applied during the (18)FDG uptake of the D9 study. PET data were analysed with statistical parametric mapping. We found an electrode insertional effect in cortical areas, while DBS resulted in a more widespread metabolic pattern. The consequences of simultaneous electrode and DBS factors revealed a combination of both effects. Therefore, the insertion metabolic effects differed from the stimulation ones, which should be considered when assessing DBS protocols. The authors thank Kenia Martinez for her help in performing the statistical analyses and the interpretation of the results; Alexandra de Francisco and Yolanda Sierra for their support in stereotaxic surgery, animal handling, and acquisition of imaging studies. This research was supported by Fundacion Mapfre, Alicia Koplowitz [FAK16/01], CIBER de Salud Mental (CIBERSAM), the Ministry of Economy and Competitiveness ISCIII-FIS Grants [PI14/00860, CPII14/00005, and PI17/01766], and Delegacion del Gobierno para el Plan Nacional sobre Drogas [PNSD 2017/085] and cofinanced by ERDF (FEDER) Funds from the European Commission, ``A way of Making Europe,´´ and Comunidad de Madrid [BRADE-CMS2013/ICE-2958]. Sí

Introduction The main therapeutic intervention for sickle cell disease (SCD) is hydroxyurea (HU). The effect of HU is largely through dose-dependent induction of fetal hemoglobin (HbF). Poor HU adherence is common among adolescents. Methods Our 6-month, two-site pilot intervention trial, “HABIT,” was led by culturally aligned community health workers (CHWs). CHWs performed support primarily through home visits, augmented by tailored text message reminders. Dyads of youth with SCD ages 10–18 years and a parent were enrolled. A customized HbF biomarker, the percentage decrease from each patients’ highest historical HU-induced HbF, “Personal best,” was used to qualify for enrollment and assess HU adherence. Two primary outcomes were as follows: (1) intervention feasibility and acceptability and (2) HU adherence measured in three ways: monthly percentage improvement toward HbF Personal best, proportion of days covered (PDC) by HU, and self-report. Results Twenty-eight dyads were enrolled, of which 89% were retained. Feasibility and acceptability were excellent. Controlling for group assignment and month of intervention, the intervention group improved percentage decrease from Personal best by 2.3% per month during months 0–4 (P = 0.30), with similar improvement in adherence demonstrated using pharmacy records. Self-reported adherence did not correlate. Dyads viewed CHWs as supportive for learning about SCD and HU, living with SCD and making progress in coordinated self-management responsibility to support a daily HU habit. Most parents and youth appreciated text message HU reminders. Conclusions The HABIT pilot intervention demonstrated feasibility and acceptability with promising effect toward improved medication adherence. Testing in a larger multisite intervention trial is warranted.

Background and aims Left ventricular hypertrophy (LVH) in hypertension is associated with a greater risk of sustained supraventricular/atrial arrhythmias. Dronedarone is an antiarrhythmic agent that was recently approved for the treatment of atrial fibrillation. However, its effect on early regression of LVH has not been reported. We tested the hypothesis that short-term administration of dronedarone induces early regression of LVH in spontaneously hypertensive rats (SHRs). Methods Ten-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where animals received dronedarone treatment (100 mg/kg) for a period of 14 days, or to a control group (SHR) where rats were given vehicle. A third group with normotensive control rats (WKY) was also added. At the end of the treatment with dronedarone we studied the cardiac anatomy and function in all the rats using transthoracic echocardiogram, cardiac metabolism using the PET/CT study (2-deoxy-2[18F]fluoro-D-glucose) and cardiac structure by histological analysis of myocyte size and collagen content. Results The hypertensive vehicle treated SHR rats developed the classic cardiac pattern of hypertensive cardiomyopathy as expected for the experimental model, with increases in left ventricular wall thickness, a metabolic shift towards an increase in glucose use and increases in myocyte and collagen content. However, the SHR-D rats showed statistically significant lower values in comparison to SHR group for septal wall thickness, posterior wall thickness, ventricular mass, glucose myocardial uptake, size of left ventricular cardiomyocytes and collagen content. All these values obtained in SHR-D rats were similar to the values measured in the normotensive WKY control group. Conclusion The results suggest by three alternative and complementary ways (analysis of anatomy and cardiac function, metabolism and histological structure) that dronedarone has the potential to reverse the LVH induced by arterial hypertension in the SHR model of compensated ventricular hypertrophy.

OBJECTIVE To investigate metabolic changes in brain networks by deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC), nucleus accumbens (NAcc) and dorsomedial thalamus (DM) using positron emission tomography (PET) in naive rats. METHODS 43 male Wistar rats underwent stereotactic surgery and concentric bipolar platinum-iridium electrodes were bilaterally implanted into one of the three brain sites. [18F]-fluoro-2-deoxy-glucose-PET (18FDG-PET) and computed tomography (CT) scans were performed at the 7th (without DBS) and 9th day (with DBS) after surgery. Stimulation period matched tracer uptake period. Images were acquired with a small-animal PET-CT scanner. Differences in glucose uptake between groups were assessed with Statistical Parametric Mapping. RESULTS DBS induced site-specific metabolic changes, although a common increased metabolic activity in the piriform cortex was found for the three brain targets. mPFC-DBS increased metabolic activity in the striatum, temporal and amygdala, and reduced it in the cerebellum, brainstem (BS) and periaqueductal gray matter (PAG). NAcc-DBS increased metabolic activity in the subiculum and olfactory bulb, and decreased it in the BS, PAG, septum and hypothalamus. DM-DBS increased metabolic activity in the striatum, NAcc and thalamus and decreased it in the temporal and cingulate cortex. CONCLUSIONS DBS induced significant changes in 18FDG uptake in brain regions associated with the basal ganglia-thalamo-cortical circuitry. Stimulation of mPFC, NAcc and DM induced different patterns of 18FDG uptake despite interacting with the same circuitries. This may have important implications to DBS research suggesting individualized target selection according to specific neural modulatory requirements.

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia’s neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy. We thank Renate Winter, Doris Zschaber and Roselies Pickert for excellent technical assistance. This research was conducted under the EraNet Neuron framework (DBS_F20rat) and supported by the BMBF, Germany (B01EW1103, 01EE1403A), Fundación Mapfre, Comunidad de Madrid and the Ministry of Economy and Competitiveness ISCIII-FIS grants (PI14/00860, CPII/00005) co-financed by ERDF (FEDER) Funds from the European Commission, ‘A way of making Europe’, Spain (PI14/00860, CPII/00005, MV1500002), the CSO-MOH, Israel (3-8580) and the Canadian Institutes of Health Research, Canada (CIHR, 110068), and co-financed by the DFG, Germany (WI 2140/1-1/2; WI 2140/2-1). Publicado

Background: Rationalization of antiangiogenics requires biomarkers. Vascular re‐normalization is one widely accepted mechanism of action for this drug class. The interstitium of tumors with abnormal vasculature is hypoxic. We sought to track vascular normalization with 18F‐misonidazole ([18F]‐FMISO, a probe that detects hypoxia) PET, in response to window‐of‐opportunity (WoO) treatment with the antiangiogenic dovitinib. Methods: Two patient‐derived pancreas xenografts (PDXs; Panc215 and Panc286) and the spontaneous breast cancer model MMTV‐PyMT were used. Animals were treated during 1 week of WoO treatment with vehicle or dovitinib, preceded and followed by [18F]‐FMISO‐PET, [18F]‐FDG‐PET, and histologic assessment (dextran extravasation, hypoxia and microvessel staining, and necrosis, cleaved caspase‐3 and Ki67 measurements). After WoO treatment, gemcitabine (pancreas)/adriamycin (breast) or vehicle was added and animals were treated until the humane endpoint. Tumor growth inhibition (TGI) and survival were the parameters studied. Results: [18F]‐FMISO SUV did not change after dovitinib‐WoO treatment compared to vehicle‐WoO (0.54 vs. 0.6) treatment in Panc215, but it decreased significantly in Panc286 (0.58 vs. 1.18; P, Highlights We describe a new technique to monitor the efficacy of antiangiogenics.This drug class currently lacks biomarkers.Antiangiogenics exert their positive effect by inducing stromal normalization.18F‐fluoromisonidazole PET is able to monitor stromal normalization.Tumors showing stromal normalization by PET experience benefit from antiangiogenics.

Grape and wine byproducts have been extensively studied for the recovery of phenolic compounds with antioxidant activity and a variety of biological actions. The selective recovery and concentration of the phenolic compounds from the liquid phase separated from further diluted winery wastes has been proposed. Adsorption onto non ionic polymeric resins and further desorption with ethanolic solutions was studied. Several commercial food grade resins were screened with the aim of selecting the most suited for the practical recovery of phenolic compounds with radical scavenging activity. Under the optimized desorption conditions (using Sepabeads SP207 or Diaion HP20 as adsorbents and eluting with 96% ethanol at 50 °C) a powdered yellow-light brown product with 50% phenolic content, expressed as gallic acid equivalents, was obtained. The radical scavenging capacity of one gram of product was equivalent to 2–3 g of Trolox The authors are grateful to grateful to the Spanish Ministry of Education and Science (Research Project reference ALG2006-05387, which had partial financial support from the FEDER funds of the European Union), and to Xunta de Galicia (Research Project Ref. PGIDIT06 TAM38301PR) for the financial support of this work. The authors thank Miguel Estévez for his excellent technical support. EC thanks the Spanish MEC (PTA-2003-02-00194) and AM thanks the MEC (PTA-2003-01-00194) and the Isidro Parga Pondal Program (Xunta de Galicia) SI