Tinostamustine (EDO-S101), an Alkylating Deacetylase Inhibitor, Enhances the Efficacy of Daratumumab in Multiple Myeloma by Upregulation of CD38 and NKG2D Ligands.

Multiple myeloma is a malignancy characterized by the accumulation of malignant plasma cells in bone marrow and the production of monoclonal immunoglobulin. A hallmark of cancer is the evasion of immune surveillance. Histone deacetylase inhibitors have been shown to promote the expression of silenced molecules and hold potential to increase the anti-MM efficacy of immunotherapy. The aim of the present work was to assess the potential effect of tinostamustine (EDO-S101), a first-in-class alkylating deacetylase inhibitor, in combination with daratumumab, an anti-CD38 monoclonal antibody (mAb), through different preclinical studies. Tinostamustine increases CD38 expression in myeloma cell lines, an effect that occurs in parallel with an increment in CD38 histone H3 acetylation levels. Also, the expression of MICA and MICB, ligands for the NK cell activating receptor NKG2D, augments after tinostamustine treatment in myeloma cell lines and primary myeloma cells. Pretreatment of myeloma cell lines with tinostamustine increased the sensitivity of these cells to daratumumab through its different cytotoxic mechanisms, and the combination of these two drugs showed a higher anti-myeloma effect than individual treatments in ex vivo cultures of myeloma patients' samples. In vivo data confirmed that tinostamustine pretreatment followed by daratumumab administration significantly delayed tumor growth and improved the survival of mice compared to individual treatments. In summary, our results suggest that tinostamustine could be a potential candidate to improve the efficacy of anti-CD38 mAbs.

El arte gráfico como medio de comunicación y cuidados en personas con demencia temprana y Alzhéimer / A arte gráfica como meio de comunicação e cuidado em pessoas com demência precoce e Alzheimer / Graphic art as a means of communication and care in people with early dementia and Alzheimer’s

El presente trabajo analiza la repercusión de la técnica de grabadono tóxica Collagraph, en personas con Demencia tempranatipo Alzhéimer, en el programa de educación artística “Retalesde una vida”. El objetivo es conectar a los participantes conprogramas de carácter cultural para fomentar la comunicacióne interacción entre participantes. La experiencia se llevó a caboen el Centro de Referencia Estatal para personas con Alzheimery otras Demencias de Salamanca (CREA). Una vez adaptadala metodología del taller a las características personales y desalud de las personas enfermas de Alzheimer, se considera lautilización del grabado genera importantes beneficios en losparticipantes, relacionados con el incremento de la inteligenciacristalizada, la conducta prosocial y la valoración positiva desí mismos, favoreciendo la inclusión social y familiar.Asimismo, el empleo del grabado puede ofrecer un soporte deayuda terapéutica individual y cooperativa a los participantes,desarrollar habilidades funcionales, sociales y cognitivas, ampliandosus recursos emocionales y disfrutar de la experiencia. A suvez fortalecen su autoestima y seguridad ante su capacidady valía. Por último, planteamos una serie de pautas para laplanificación e implementación de este proceso artístico paraque sirva de referente a profesionales de la salud.(AU)

The present work analyzes the repercussion of the non-toxic engraving technique Collagraph, in people with EarlyAlzheimer’s Dementia, in the artistic education program “Retalesde una vida”. The objective is to connect the participants withprograms of a cultural nature to encourage communication and interaction between participants. The experience wascarried out at the State Reference Center for people withAlzheimer’s and other Dementias of Salamanca (CREA). Oncethe methodology of the workshop has been adapted to thepersonal and health characteristics of people with Alzheimer'sdisease, it is considered that the use of engraving generatesimportant benefits in the participants, related to the increasein crystallized intelligence, prosocial behavior and positiveassessment. of themselves, favoring social and family inclusion.Likewise, the use of engraving can offer support for individualand cooperative therapeutic help to the participants, developfunctional, social and cognitive skills, expanding theiremotional resources and enjoying the experience. In turn,they strengthen their self-esteem and security in the faceof their ability and worth. Finally, we propose a series ofguidelines for the planning and implementation of this artisticprocess so that it serves as a reference for health professionals.(AU)

O presente trabalho analisa a repercussão da técnica degravura atóxica Collagraph, em pessoas com DemênciaInicial de Alzheimer, no programa de educação artística“Retales de una vida”. O objetivo é conectar os participantes aprogramas de cunho cultural para estimular a comunicação ea interação entre os participantes. A experiência foi realizadano Centro Estadual de Referência para Pessoas com Alzheimere outras Demências de Salamanca (CREA). Uma vez quea metodologia da oficina foi adaptada às característicaspessoais e de saúde das pessoas com doença de Alzheimer,considerase que o uso da gravura gera importantes benefíciosnos participantes, relacionados ao aumento da inteligênciacristalizada, comportamento prósocial e avaliação positivade si mesmos, favorecendo a inclusão social e familiar.Da mesma forma, o uso da gravura pode oferecer suporte paraajuda terapêutica individual e cooperativa aos participantes,desenvolver habilidades funcionais, sociais e cognitivas, ampliandoseus recursos emocionais e desfrutando da experiência. Porsua vez, fortalecem sua auto-estima e segurança diante de suacapacidade e valor. Por fim, propomos uma série de diretrizespara o planejamento e implementação desse processo artísticopara que sirva de referência para os profissionais de saúde.(AU)

[Impacto de la pandemia de la COVID-19 en los sistemas de vigilancia epidemiologica de la infección por vih en España.] / Impact of the COVID-19 pandemic on the epidemiological surveillance systems of hiv infection in Spain.

OBJECTIVE: The COVID-19 pandemic indirectly affected other communicable diseases, such as human immunodeficiency virus (HIV) infection. The aim of this paper was to evaluate the impact of the COVID-19 pandemic on the epidemiological surveillance of HIV through epidemiological indicators. METHODS: Data collected in the New HIV Diagnosis Information System (SINIVIH, acronym in Spanish) in the period 2013-2021 was analyzed. The epidemiological indicators analyzed were: 1) Reporting delay of new diagnoses; 2) Under diagnosis of cases, calculated per month of diagnosis and for each year of diagnosis; 3) Late diagnosis, cases diagnosed with less than 350 CD4 cell/mm3. RESULTS: Regarding the reporting delay of new diagnoses, in 2022 2,770 diagnoses were reported in 2020, 43.8% more than those reported in 2021 for that year. The cases diagnosed per month between 2016 and 2019 followed a constant trend. In 2020, a significant decrease in diagnoses was observed between March and May that was not recovered after correcting for reporting delay. When comparing the rates of cases diagnosed in 2013 with the successive years, a continuous decrease was interrupted in the last year of the study period. The percentage of cases with late diagnosis had remained stable in the study period (between 46% and 50%), and a decrease in this percentage was observed after correcting for reporting delay. CONCLUSIONS: The epidemiological surveillance of HIV suffered a significant reporting delay. A decrease in cases diagnosed is confirmed, partly due to lockdown and lack of access to the health system. Changes on late diagnosis is not observed.

OBJECTIVE: La pandemia de la COVID-19 afectó de forma indirecta a otras enfermedades transmisibles, como la infección por el virus de la inmunodeficiencia humana (VIH). El objetivo de este estudio fue evaluar el impacto de la pandemia de la COVID-19 en la vigilancia epidemiológica del VIH a través de indicadores epidemiológicos. METHODS: Se analizaron los datos recogidos en el Sistema de Información de Nuevos Diagnósticos de VIH (SINIVIH) en el periodo 2013-2021. Los indicadores epidemiológicos analizados fueron: 1) Retraso en la notificación de nuevos diagnósticos; 2) Infradiagnóstico de caso, calculado por mes y por cada año de diagnóstico; 3) Diagnóstico tardío, casos diagnosticados con menos de 350 células CD4/mm3. RESULTS: Respecto al retraso en la notificación de nuevos diagnósticos, en 2022 se notificaron 2.770 casos diagnosticados en 2020, un 43,8% más respecto a los notificados en 2021 para ese año. Los casos diagnosticados por mes entre 2016 y 2019 seguían una tendencia constante. En 2020 se observó un descenso importante de diagnósticos entre marzo y mayo que no se recuperó al corregir por retraso en la notificación. Al comparar las tasas de casos diagnosticados en 2013 con los años sucesivos, se observó un descenso continuo que se interrumpía en el último año del periodo de estudio. El porcentaje de casos con diagnóstico tardío se mantuvo estable en el periodo de estudio (entre el 46% y el 50%), observándose un descenso al corregir por retraso en la notificación. CONCLUSIONS: La vigilancia epidemiológica del VIH sufrió un importante retraso en la notificación. Se constata un descenso en los casos diagnosticados, en parte debido al confinamiento y la falta de acceso a pruebas diagnósticas. No se observan cambios en el diagnóstico tardío.

Impacto de la pandemia de la COVID-19 en los sistemas de vigilancia epidemiologica de la infección por VIH en España / Impact of the COVID-19 pandemic on the epidemiological surveillance systems of HIV infection in Spain

Fundamentos: La pandemia de la COVID-19 afectó de forma indirecta a otras enfermedades transmisibles, como la infección por el virus de la inmunodeficiencia humana (VIH). El objetivo de este estudio fue evaluar el impacto de la pandemia de la COVID-19 en la vigilancia epidemiológica del VIH a través de indicadores epidemiológicos. Métodos: Se analizaron los datos recogidos en el Sistema de Información de Nuevos Diagnósticos de VIH (SINIVIH) en el periodo 2013-2021. Los indicadores epidemiológicos analizados fueron: 1) Retraso en la notificación de nuevos diagnósticos; 2) Infradiagnóstico de caso, calculado por mes y por cada año de diagnóstico; 3) Diagnóstico tardío, casos diagnosticados con menos de 350 células CD4/mm3.Resultados: Respecto al retraso en la notificación de nuevos diagnósticos, en 2022 se notificaron 2.770 casos diagnosticados en 2020, un 43,8% más respecto a los notificados en 2021 para ese año. Los casos diagnosticados por mes entre 2016 y 2019 seguían una tendencia constante. En 2020 se observó un descenso importante de diagnósticos entre marzo y mayo que no se recuperó al corregir por retraso en la notificación. Al comparar las tasas de casos diagnosticados en 2013 con los años sucesivos, se observó un descenso continuo que se interrumpía en el último año del periodo de estudio. El porcentaje de casos con diagnóstico tardío se mantuvo estable en el periodo de estudio (entre el 46% y el 50%), observándose un descenso al corregir por retraso en la notificación. Conclusiones: La vigilancia epidemiológica del VIH sufrió un importante retraso en la notificación. Se constata un descenso en los casos diagnosticados, en parte debido al confinamiento y la falta de acceso a pruebas diagnósticas. No se observan cambios en el diagnóstico tardío.(AU)

Background: The COVID-19 pandemic indirectly affected other communicable diseases, such as human immunodeficiency virus (HIV) infection. The aim of this paper was to evaluate the impact of the COVID-19 pandemic on the epidemiological surveillance of HIV through epidemiological indicators. Methods: Data collected in the New HIV Diagnosis Information System (SINIVIH, acronym in Spanish) in the period 2013-2021 was analyzed. The epidemiological indicators analyzed were: 1) Reporting delay of new diagnoses; 2) Under diagnosis of cases, calculated per month of diagnosis and for each year of diagnosis; 3) Late diagnosis, cases diagnosed with less than 350 CD4 cell/mm3. Results: Regarding the reporting delay of new diagnoses, in 2022 2,770 diagnoses were reported in 2020, 43.8% more than those reported in 2021 for that year. The cases diagnosed per month between 2016 and 2019 followed a constant trend. In 2020, a significant decrease in diagnoses was observed between March and May that was not recovered after correcting for reporting delay. When comparing the rates of cases diagnosed in 2013 with the successive years, a continuous decrease was interrupted in the last year of the study period. The percentage of cases with late diagnosis had remained stable in the study period (between 46% and 50%), and a decrease in this percentage was observed after correcting for reporting delay.Conclusions: The epidemiological surveillance of HIV suffered a significant reporting delay. A decrease in cases diagnosed is confirmed, partly due to lockdown and lack of access to the health system. Changes on late diagnosis is not observed.(AU)

Hypovitaminosis D in persons with Down syndrome and autism spectrum disorder.

BACKGROUND: Plasma levels of vitamin D have been reported to be low in persons with Down syndrome (DS) and existing data is limited to small and homogenous cohorts. This is of particular importance in persons with DS given the high rates of autoimmune disease in this population and the known relationship between vitamin D and immune function. This study sought to investigate vitamin D status in a multi-center cohort of individuals with DS and compare them to individuals with autism spectrum disorder (ASD) and neurotypical (NT) controls. METHODS: A retrospective, multi-center review was performed. The three sites were located at latitudes of 42.361145, 37.44466, and 34.05349. Patients were identified by the International Classification of Diseases (ICD)-9 or ICD-10 codes for DS, ASD, or well-child check visits for NT individuals. The first vitamin D 25-OH level recorded in the electronic medical record (EMR) was used in this study as it was felt to be the most reflective of a natural and non-supplemented state. Vitamin D 25-OH levels below 30 ng/mL were considered deficient. RESULTS: In total, 1624 individuals with DS, 5208 with ASD, and 30,775 NT controls were identified. Individuals with DS had the lowest mean level of vitamin D 25-OH at 20.67 ng/mL, compared to those with ASD (23.48 ng/mL) and NT controls (29.20 ng/mL) (p < 0.001, 95% CI: -8.97 to -6.44). A total of 399 (24.6%) individuals with DS were considered vitamin D deficient compared to 1472 (28.3%) with ASD and 12,397 (40.3%) NT controls (p < 0.001, 95% CI: -5.43 to -2.36). Individuals with DS with higher body mass index (BMI) were found to be more likely to have lower levels of vitamin D (p < 0.001, 95% CI: -0.3849 to -0.1509). Additionally, having both DS and a neurologic diagnosis increased the likelihood of having lower vitamin D levels (p < 0.001, 95% CI: -5.02 to -1.28). Individuals with DS and autoimmune disease were much more likely to have lower vitamin D levels (p < 0.001, 95% CI: -6.22 to -1.55). Similarly, a history of autoimmunity in a first-degree relative also increased the likelihood of having lower levels of vitamin D in persons with DS (p = 0.01, 95% CI: -2.45 to -0.63). CONCLUSIONS: Individuals with DS were noted to have hypovitaminosis D in comparison to individuals with ASD and NT controls. Associations between vitamin D deficiency and high BMI, personal autoimmunity, and familial autoimmunity were present in individuals with DS.

Adverse childhood experiences and the development of Down syndrome regression disorder.

Down syndrome regression disorder (DSRD) is a clinical symptom cluster of acute or subacute neurocognitive regression in otherwise health persons with Down syndrome. The objective of this study was to evaluate if adverse childhood experiences (ACEs) were more prevalent in children with DSRD than those with DS alone. A survey-based, cohort-based study was performed. Caregivers of individuals with DSRD with onset of symptoms between age 10 and 30 years and DS alone were administered the ACEs questionnaire via an online REDCap survey. A total of 159 responses were collected after excluding incomplete surveys and those not meeting criteria for DSRD. Individuals with DSRD were not more likely to experience ACEs (p = 0.18, 95% confidence interval [CI]: 0.43-1.17). In those with ACEs prior to the onset of symptoms, the median time prior was 7 months (interquartile range: 5-10). Individuals with DSRD were more likely to report three or more ACEs (52, 33%) compared to those with DS alone (39, 22%) (p = 0.02, 95% CI: 1.08-2.87). Exposure to ACEs were not predictive of response to particular therapeutic interventions although those with multiple ACEs 3 months prior to the onset of symptoms was associated with lower response rates to benzodiazepines and immunotherapy (p = 0.02, 95% CI: -3.64--1.13). This study provides preliminary data that individuals with DSRD experience ACEs at a similar rate to individuals with only DS alone, although three or more ACEs, often preceding the onset of symptoms, was more prevalent in individuals with DSRD.

Memorias de mujer: Construcción e identidad del género mujer a través del cine español / Memorias de Mujer: Construction and Identity of the Female Gender Through Spanish Cinema

El cine encarna la vida real en todo aquello que imaginamos, por ello, desde el Máster en Educación Artística en Instituciones Sociales y Culturales de la Universidad Complutense de Madrid, se propone desarrollar un proyecto intergeneracional, Memorias de Mujer, que utiliza el cine español como herramienta mediadora, para analizar los procesos de construcción e identidad de género y expresar en un documento audiovisual la experiencia reflexiva, el cual es evaluado en el presente trabajo. Así, se opta por un diseño de investigación mixto y experimental1, establecido desde el paradigma de la investigación-acción, en torno a unos principios metodológicos, que organizan las acciones en torno a las variables que describen el hecho a investigar. Los resultados del estudio, analizados mediante la técnica cualitativa del panel, permiten afirmar que la propuesta cinematográfica ha funcionado. El cine fórum ha permitido abordar la evolución del rol de la mujer, así como compartir intersubjetividades e imaginarios con mujeres de otras generaciones. (AU)

The cinema embodies real life in everything we imagine, for this reason, from the Master’s degree in Art Education in Social and Cultural Institutions of the Complutense University of Madrid, it is proposed to develop an intergenerational project, Memorias de Mujer, which uses Spanish cinema as a mediating tool, to analyze the processes of construction and gender identity and express the reflective experience in an audiovisual document, which is evaluated in this work. Thus, a mixed and experimental research design is chosen1, established from the action-research paradigm, around methodological principles, which organize the actions around the variables that describe the fact at hand. research. The results of the study, analyzed using the qualitative panel technique, allow us to affirm that the cinematographic proposal has worked. The cinema forum has made it possible to address the evolution of the role of women, as well as to share intersubjectivities and imaginaries with women of other generations. (AU)

Stroma-Mediated Resistance to S63845 and Venetoclax through MCL-1 and BCL-2 Expression Changes Induced by miR-193b-3p and miR-21-5p Dysregulation in Multiple Myeloma.

BH3-mimetics targeting anti-apoptotic proteins such as MCL-1 (S63845) or BCL-2 (venetoclax) are currently being evaluated as effective therapies for the treatment of multiple myeloma (MM). Interleukin 6, produced by mesenchymal stromal cells (MSCs), has been shown to modify the expression of anti-apoptotic proteins and their interaction with the pro-apoptotic BIM protein in MM cells. In this study, we assess the efficacy of S63845 and venetoclax in MM cells in direct co-culture with MSCs derived from MM patients (pMSCs) to identify additional mechanisms involved in the stroma-induced resistance to these agents. MicroRNAs miR-193b-3p and miR-21-5p emerged among the top deregulated miRNAs in myeloma cells when directly co-cultured with pMSCs, and we show their contribution to changes in MCL-1 and BCL-2 protein expression and in the activity of S63845 and venetoclax. Additionally, direct contact with pMSCs under S63845 and/or venetoclax treatment modifies myeloma cell dependence on different BCL-2 family anti-apoptotic proteins in relation to BIM, making myeloma cells more dependent on the non-targeted anti-apoptotic protein or BCL-XL. Finally, we show a potent effect of the combination of S63845 and venetoclax even in the presence of pMSCs, which supports this combinatorial approach for the treatment of MM.

Impact of GABAA and GABAB Inhibition on Cortical Dynamics and Perturbational Complexity during Synchronous and Desynchronized States.

Quantitative estimations of spatiotemporal complexity of cortical activity patterns are used in the clinic as a measure of consciousness levels, but the cortical mechanisms involved are not fully understood. We used a version of the perturbational complexity index (PCI) adapted to multisite recordings from the ferret (either sex) cerebral cortex in vitro (sPCI) to investigate the role of GABAergic inhibition in cortical complexity. We studied two dynamical states: slow-wave activity (synchronous state) and desynchronized activity, that express low and high causal complexity respectively. Progressive blockade of GABAergic inhibition during both regimes revealed its impact on the emergent cortical activity and on sPCI. Gradual GABAA receptor blockade resulted in higher synchronization, being able to drive the network from a desynchronized to a synchronous state, with a progressive decrease of complexity (sPCI). Blocking GABAB receptors also resulted in a reduced sPCI, in particular when in a synchronous, slow wave state. Our findings demonstrate that physiological levels of inhibition contribute to the generation of dynamical richness and spatiotemporal complexity. However, if inhibition is diminished or enhanced, cortical complexity decreases. Using a computational model, we explored a larger parameter space in this relationship and demonstrate a link between excitatory/inhibitory balance and the complexity expressed by the cortical network.SIGNIFICANCE STATEMENT The spatiotemporal complexity of the activity expressed by the cerebral cortex is a highly revealing feature of the underlying network's state. Complexity varies with physiological brain states: it is higher during awake than during sleep states. But it also informs about pathologic states: in disorders of consciousness, complexity is lower in an unresponsive wakefulness syndrome than in a minimally conscious state. What are the network parameters that modulate complexity? Here we investigate how inhibition, mediated by either GABAA or GABAA receptors, influences cortical complexity. And we do this departing from two extreme functional states: a highly synchronous, slow-wave state, and a desynchronized one that mimics wakefulness. We find that there is an optimal level of inhibition in which complexity is highest.

Modulation of cortical slow oscillations and complexity across anesthesia levels.

The ability of different groups of cortical neurons to engage in causal interactions that are at once differentiated and integrated results in complex dynamic patterns. Complexity is low during periods of unconsciousness (deep sleep, anesthesia, unresponsive wakefulness syndrome) in which the brain tends to generate a stereotypical pattern consisting of alternating active and silent periods of neural activity-slow oscillations- and is high during wakefulness. But how is cortical complexity built up? Is it a continuum? An open question is whether cortical complexity can vary within the same brain state. Here we recorded with 32-channel multielectrode arrays from the cortical surface of the mouse and used both spontaneous dynamics (wave propagation entropy and functional complexity) and a perturbational approach (a variation of the perturbation complexity index) to measure complexity at different anesthesia levels. Variations in anesthesia level within the bistable regime of slow oscillations (0.1-1.5 Hz) resulted in a modulation of the slow oscillation frequency. Both perturbational and spontaneous complexity increased with decreasing anesthesia levels, in correlation with the decrease in coherence of the underlying network. Changes in complexity level are related to, but not dependent on, changes in excitability. We conclude that cortical complexity can vary within a single brain state dominated by slow oscillations, building up to the higher complexity associated with consciousness.

Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma.

BACKGROUND: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. METHODS: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. RESULTS: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. CONCLUSIONS: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.

Physiological and metabolic responses to hypersalinity reveal interpopulation tolerance in the green macroalga Ulva compressa with different pollution histories.

There is scarce investigation addressing interpopulation tolerance responses to address the influence of a history of chronic stress exposure, as that occurring in polluted environments, in photoautotrophs. We evaluated ecophysiological (photosynthetic activity) and metabolic (oxidative stress and damage) responses of two populations of green macroalga Ulva compressa from polluted (Ventanas) and non-polluted (Cachagua) localions of central Chile, and exposed to controlled hypersalinity conditions of 32 (control), 42, 62 and 82 psu (practical salinity units) for 6 h, 48 h and 6 d. Both primary production (ETRmax) and photosynthetic efficiency (αETR) were generally higher in the population from Cachagua compared to Ventanas at all times and salinities. Moreover, at most experimental times and salinities the population from Ventanas had greater levels of H2O2 and lipid peroxidation that individuals from Cachagua. Total ascorbate was higher in the population of Cachagua than Ventanas at 42 and 82 psu after 6 and 48 h, respectively, while at 6 d concentrations were similar between both populations at all salinities. Total glutathione was greater in both populations after 6 h at all salinities, but at 48 h its concentrations were higher only in the population from Cachagua, a trend that was maintained at 6 d under 82 psu only. Reduced and oxidized ascorbate (ASC and DHA, respectively) and glutathione (GSH and GSSG, respectively) demonstrated similar patterns between U. compressa populations, with an increase oxidation with greater salinities but efficient recycling to maintain sufficient batch of ASC and GSH. When assessing the expression of antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and dehydroascorbate reductase (DHAR), while the population of Ventanas displayed a general trend of upregulation with increasing salinities along the experiments, U. compressa from Cachagua revealed patterns of downregulation. Results demonstrated that although both populations were still viable after the applied hypersalinities during all experimental times, biological performance was usually more affected in the population from the Ventanas than Cachagua, likely due to a depressed baseline metabolism after a long history of exposition to environmental pollution.

Being the Victim of Intimate Partner Violence in Virtual Reality: First- Versus Third-Person Perspective.

Immersive virtual reality is widely used for research and clinical purposes. Here we explored the impact of an immersive virtual scene of intimate partner violence experienced from the victim's perspective (first person), as opposed to witnessing it as an observer (third person). We are ultimately interested in the potential of this approach to rehabilitate batterers and in understanding the mechanisms underlying this process. For this, non-offender men experienced the scene either from the perspective of the victim's virtual body (a female avatar), which moved synchronously with the participants' real movements, or from the perspective of an observer, while we recorded their behavior and physiological responses. We also evaluated through questionnaires, interviews and implicit association tests their subjective impressions and potential pre/post changes in implicit gender bias following the experience. We found that in all participants, regardless of perspective, the magnitude of the physiological reactions to virtual threatening stimuli was related to how vulnerable they felt for being a woman, the sensation that they could be assaulted, how useful the scene could be for batterer rehabilitation, and how different it would have been to experience the scenario on TV. Furthermore, we found that their level of identification with the female avatar correlated with the decrease in prejudice against women. Although the first-person perspective (1PP) facilitated taking the scene personally, generated a sensation of fear, helplessness, and vulnerability, and tended to induce greater behavioral and physiological reactions, we show that the potential for batterer rehabilitation originates from presence and identification with the victim, which in turn is more easily, but not exclusively, achieved through 1PP. This study is relevant for the development of advanced virtual reality tools for clinical purposes.

Cápsulas de arte: memoria frente al Alzheimer / Art capsule: memory to fight Alzheimer's / Cápsula de arte: memória contra a doença de Alzheimer

El presente trabajo analiza, a través de una técnica de panel, denominada "de cohorte", las reflexiones de las investigadoras españolas en el campo del Arte y del Alzheimer, con el fin de estudiar su trayectoria profesional y de relacionar las conclusiones de sus trabajos, con los resultados del Informe Mundial de la Organización Mundial de la Salud (OMS), el cual establece, por vez primera, una correlación positiva entre las variables arte y salud, situando el compromiso ético del arte, en la vanguardia de la investigación. Las conclusiones derivadas del estudio muestran, cómo al hablar de sí mismas, las investigadoras se definen no sólo como educadoras artísticas, sino también como cuidadoras, reconociendo el papel del contexto, esto es de su propia bibliografía, como determinante en las investigaciones que han realizado en el campo de la Educación Artística aplicada al Alzheimer.(AU)

The objective of this study is to analyze—through a panel technique called "cohort"—the authors' reflections on the fields of Arts and Alzheimer's in order to study their professional path and correlate the conclusions of their work with the results presented on the Health Evidence Network synthesis report 67 of the World Health Organization (WHO). For the first time, the report establishes a positive correlation between the arts and health, highlighting the importance of the ethical commitment of the arts to the research. The conclusions of this study show how the researchers refer to themselves as both "arts educators" and "caregivers," acknowledging the decisive role of context, i.e. their won biographies, to the research conducted in the field of Arts Education applied to Alzheimer's.(AU)

O presente trabalho analisa, por meio de uma técnica de painel denominada "coorte", as reflexões das investigadoras espanholas no campo da Arte e do Alzheimer, com o fim de estudar o seu percurso profissional e de relacionar as conclusões dos seus trabalhos com os resultados do Relatório Mundial da Organização Mundial da Saúde (OMS), que estabelece, pela primeira vez, uma correlação positiva entre as variáveis arte e saúde, situando o compromisso ético da arte na vanguarda da investigação. As conclusões resultantes do estudo mostram como, ao falar de si mesmas, as pesquisadoras definem-se não só como educadoras artísticas, mas também como cuidadoras, reconhecendo o papel do contexto, isto é, de suas próprias biografias como determinantes nas investigações que realizaram no domínio da Educação Artística aplicada ao Alzheimer.(AU)

MAPK Pathway under Chronic Copper Excess in Green Macroalgae (Chlorophyta): Involvement in the Regulation of Detoxification Mechanisms.

Following the physiological complementary/parallel Celis-Plá et al., by inhibiting extracellular signal regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and cytokinin specific binding protein (p38), we assessed the role of the mitogen-activated protein kinases (MAPK) pathway in detoxification responses mediated by chronic copper (10 µM) in U. compressa. Parameters were taken at 6, 24, and 48 h, and 6 days (d). H2O2 and lipid peroxidation under copper and inhibition of ERK, JNK, or p38 alone increased but recovered by the sixth day. By blocking two or more MAPKs under copper, H2O2 and lipid peroxidation decayed even below controls. Inhibition of more than one MAPK (at 6 d) caused a decrease in total glutathione (reduced glutathione (GSH) + oxidised glutathione (GSSG)) and ascorbate (reduced ascorbate (ASC) + dehydroascorbate (DHA)), although in the latter it did not occur when the whole MAPK was blocked. Catalase (CAT), superoxide dismutase (SOD), thioredoxin (TRX) ascorbate peroxidase (APX), dehydroascorbate reductase (DHAR), and glutathione synthase (GS), were downregulated when blocking more than one MAPK pathway. When one MAPK pathway was blocked under copper, a recovery and even enhancement of detoxification mechanisms was observed, likely due to crosstalk within the MAPKs and/or other signalling processes. In contrast, when more than one MAPK pathway were blocked under copper, impairment of detoxification defences occurred, demonstrating that MAPKs were key signalling mechanisms for detoxification in macroalgae.

MAPK Pathway under Chronic Copper Excess in Green Macroalgae (Chlorophyta): Influence on Metal Exclusion/Extrusion Mechanisms and Photosynthesis.

There is currently no information regarding the role that whole mitogen activated protein kinase (MAPK) pathways play in counteracting environmental stress in photosynthetic organisms. To address this gap, we exposed Ulva compressa to chronic levels of copper (10 µM) specific inhibitors of Extracellular Signal Regulated Kinases (ERK), c-Jun N-terminal Kinases (JNK), and Cytokinin Specific Binding Protein (p38) MAPKs alone or in combination. Intracellular copper accumulation and photosynthetic activity (in vivo chlorophyll a fluorescence) were measured after 6 h, 24 h, 48 h, and 6 days of exposure. By day 6, when one (except JNK) or more of the MAPK pathways were inhibited under copper stress, there was a decrease in copper accumulation compared with algae exposed to copper alone. When at least two MAPKs were blocked, there was a decrease in photosynthetic activity expressed in lower productivity (ETRmax), efficiency (αETR), and saturation of irradiance (EkETR), accompanied by higher non-photochemical quenching (NPQmax), compared to both the control and copper-only treatments. In terms of accumulation, once the MAPK pathways were partially or completely blocked under copper, there was crosstalk between these and other signaling mechanisms to enhance metal extrusion/exclusion from cells. Crosstalk occurred among MAPK pathways to maintain photosynthesis homeostasis, demonstrating the importance of the signaling pathways for physiological performance. This study is complemented by a parallel/complementary article Rodríguez-Rojas et al. on the role of MAPKs in copper-detoxification.

Altered slow (<1 Hz) and fast (beta and gamma) neocortical oscillations in the 3xTg-AD mouse model of Alzheimer's disease under anesthesia.

The 3xTg-AD mouse model reproduces the main features associated with the etiology of familial Alzheimer's disease (AD). To investigate whether these features imply functional cortical network alterations and their evolution with age, we studied spontaneous slow oscillations, activity that integrates cellular and network properties. We quantified different parameters of the emergent slow oscillations-alternating Up and Down states-and of the embedded beta-gamma rhythms of 3xTg-AD and wild-type mice at 7 and 20 months of age. Most group differences occurred at 20 months of age: 3xTg-AD mice presented lower oscillatory frequency, higher cycle variability, and reduced relative (Up/Down) firing rate with respect to controls. The high-frequency analysis revealed a shift toward lower frequencies in older 3xTg-AD animals, reminiscent of one of the electroencephalography hallmarks of patients with AD. This first systematic characterization of the cortical emergent rhythms in 3xTg-AD strain provides insights into the network mechanisms underlying associated network activity alterations.

Survey of chronic pain in Chile - prevalence and treatment, impact on mood, daily activities and quality of life.

Background and aims The prevalence of chronic non-cancer pain has not been specifically reported in Chile. Methods In order to assess its prevalence and impact, we designed a tool based on previously published survey studies. We analyzed a sample of 784 subjects to determine the prevalence of chronic non-cancer pain, with a maximum variability of 50%, a confidence interval (CI) of 95%, and an estimation error of 3.5%. Finally, a cross-sectional cell phone survey was conducted on a nationally representative probability sample of 865 subjects of over 18 years, in November 2013. The prevalence of chronic non-cancer pain was estimated by using expansion factors according to national projections by age group and gender, from the Chilean National Institute of Statistics for the year 2010. Results The estimated prevalence of chronic non-cancer pain was 32.1% (95% CI: 26.5-36.0). The respondents with chronic non-cancer pain presented the following results: 65.7% had moderate pain, and 20.8%, severe pain; 65.6% had somatic pain, 31.7% neuropathic pain, and 2.7% visceral pain. Approximately 70% reported they were receiving some kind of pharmacological treatment with certain frequency. In 64.9%, medication was prescribed by a physician. The prevalence of sick leave in workers was 30.22%, with a median duration of 14 days (interquartile range: 14; range: 1-60). Conclusions Chronic non-oncological pain occurs in 32% of Chilean adults. These figures provide the first measurement of chronic non-cancer pain in the Chilean population. Implications Chronic non-oncological pain impact as a public health problem is revealed, given the high prevalence found, and the elevated private and social costs involved.

Beta and Gamma Oscillations in Prefrontal Cortex During NMDA Hypofunction: An In Vitro Model of Schizophrenia Features.

NMDA receptor (NMDAr) hypofunction has been widely used as a schizophrenia model. Decreased activation of NMDAr is associated with a disrupted excitation/inhibition balance in the prefrontal cortex and with alterations in gamma synchronization. Our aim was to investigate whether this phenomenon could be reproduced in the spontaneous oscillatory activity generated by the local prefrontal network in vitro and, if so, to explore the effects of antipsychotics on the resulting activity. Extracellular recordings were obtained from prefrontal cortex slices bathed in in vivo-like ACSF solution. Slow (<1 Hz) oscillations consisting of interspersed Up (active) and Down (silent) states spontaneously emerged. Fast-frequency oscillations (15-90 Hz) occurred during Up states. We explored the effects of the NMDAr antagonist MK-801 on the spontaneously generated activity. Bath-applied MK-801 induced a dose-dependent decrease in Up-state duration and in the frequency of Up states. However, the beta/gamma power during Up states significantly increased; this increase was in turn prevented by the antipsychotic drug clozapine. The increased beta/gamma power with NMDAr blockade implies that NMDAr activation in physiological conditions prevents hypersynchronization in this frequency range. High-frequency hypersynchronization following NMDAr blockade occurring in cortical slices suggests that-at least part of-the underlying mechanisms of this schizophrenia feature persist in the local cortical circuit, even in the absence of long-range cortical or subcortical inputs. The observed action of clozapine decreasing hypersynchronization in the local circuit may be one of the mechanisms of action of clozapine in preventing schizophrenia symptoms derived from NMDA hypofunction.