An Intercellular Flow of Glutathione Regulated by Interleukin 6 Links Astrocytes and the Liver in the Pathophysiology of Amyotrophic Lateral Sclerosis

Oxidative stress has been proposed as a major mechanism of damage to motor neurons associated with the progression of amyotrophic lateral sclerosis (ALS). Astrocytes are the most numerous glial cells in the central nervous system and, under physiological conditions, protect neurons from oxidative damage. However, it is uncertain how their reactive phenotype may affect motor neurons during ALS progression. In two different ALS mouse models (SOD1G93A and FUS-R521C), we found that increased levels of proinflammatory interleukin 6 facilitate glutathione (GSH) release from the liver to blood circulation, which can reach the astrocytes and be channeled towards motor neurons as a mechanism of antioxidant protection. Nevertheless, although ALS progression is associated with an increase in GSH efflux from astrocytes, generation of reactive oxygen species also increases, suggesting that as the disease progresses, astrocyte-derived oxidative stress could be key to motor-neuron damage

Observational study of HR+/HER2− metastatic breast cancer patients treated with abemaciclib in Spain in the Named Patient Use Program (AbemusS)

Metastatic breast cancer; Abemaciclib; EffectivenessCàncer de mama metastàtic; Abemaciclib; EficàciaCáncer de mama metastásico; Abemaciclib; EficaciaIntroduction/objectives To describe abemaciclib use in patients with hormone receptor-positive, human epidermal growth factor receptor-negative (HR+/HER2−) metastatic breast cancer (mBC) who participated in the Named Patient Use program (NPU) in Spain. Material and methods This retrospective study was based on medical record review of patients across 20 centers during 2018/2019. Patients were followed up until death, enrolment in a clinical trial, loss of follow-up or study end. Clinical and demographic characteristics, treatment patterns and abemaciclib effectiveness were analyzed; time-to-event and median times were estimated using the Kaplan–Meier (KM) method. Results The study included 69 female patients with mBC (mean age 60.4 ± 12.4 years), 86% of whom had an initial diagnosis of early BC and 20% had an ECOG ≥ 2. Median follow-up was 23 months (range 16–28). Metastases were frequently observed in bone (79%) and visceral tissue (65%), with 47% having metastases in > 2 sites. Median number of treatment lines before abemaciclib was 6 (range 1–10). Abemaciclib monotherapy was received by 72% of patients and combination therapy with endocrine therapy by 28% of patients; 54% of patients required dose adjustments, with a median time to first adjustment of 1.8 months. Abemaciclib was discontinued in 86% of patients after a median of 7.7 months (13.2 months for combination therapy and 7.0 months for monotherapy) mainly due to disease progression (69%). Conclusion These results suggest that abemaciclib is effective, as monotherapy and in combination, for patients with heavily pretreated mBC, consistent with clinical trial results.Sponsorship for this study was funded by Lilly. It was conducted with the support of the Clinical Research Organization IQVIA for the following activities: protocol development, site monitoring and statistical analysis

MAGIC VHE Gamma-Ray Observations Of Binary Systems

There are several types of Galactic sources that can potentially accelerate charged particles up to GeV and TeV energies. We present here the results of our observations of the source class of gamma-ray binaries and the subclass of binary systems known as novae with the MAGIC telescopes. Up to now novae were only detected in the GeV range. This emission can be interpreted in terms of an inverse Compton process of electrons accelerated in a shock. In this case it is expected that protons in the same conditions can be accelerated to much higher energies. Consequently they may produce a second component in the gamma-ray spectrum at TeV energies. The focus here lies on the four sources: nova V339 Del, SS433, LS I +61 303 and V404 Cygni. The binary system LS I +61 303 was observed in a long-term monitoring campaign for 8 years. We show the newest results on our search for superorbital variability, also in context with contemporaneous optical observations. Furthermore, we present the observations of the only super-critical accretion system known in our galaxy: SS433. Finally, the results of the follow-up observations of the microquasar V404 Cygni during a series of outbursts in the X-ray band and the ones of the nova V339 Del will be discussed in these proceedings.Comment: Proceedings of the 35th International Cosmic Ray Conference (ICRC 2017), Bexco, Busan, Korea (arXiv:1708.05153

Aplicación de la tecnología 3D en la restauración del conjunto escultórico Los Portadores de la Antorcha, de la Ciudad Universitaria de Madrid

El conjunto escultórico Los Portadores de la Antorcha, realizado por la escultora estadounidense Anna Vaughn Hyatt Huntington, sufrió hace tres años el robo de uno de sus elementos constitutivos más importantes: la antorcha que portaba la figura situada en el plano inferior. Un equipo de investigación ha llevado a cabo la restitución de la pieza faltante y, para ello, ha empleado una combinación de la tecnología 3D con los tradicionales métodos de moldeo. Como planteamiento previo, se planteó la digitalización, mediante escáner 3D o fotogrametría, de algunas de las antorchas correspondientes a otras versiones que de la escultura existen en nuestro país (Valencia), así como en América. Debido a la imposibilidad, hasta el momento, de optar por esta medida, finalmente se ha puesto en práctica otra opción, que ha consistido en la realización del modelado 3D de la antorcha a partir de las seis fotografías de las que se disponía. Una vez se dispuso de este modelo 3D, se realizó el fresado 3D de la llama, así como el torneado de la parte inferior. De este modelo en resina de poliuretano se realizó su molde y después el vaciado final y mediante el empleo de una resina epoxi con filtro UV, de manera que el color de aluminio de la pieza permanezca lo más estable posible

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps

Integración de Datos Psicológicos y Sociales en la Historia Clínica Electrónica de Personas con VIH/SIDA

Este artículo realiza un análisis de la situación actual de la enfermedad del SIDA, destacando la necesaria incorporación de aspectos psicológicos y sociales en el tratamiento de las personas infectadas con el objetivo de aumentar su calidad de vida. Esta incorporación nos llevaría a un tratamiento integral de los pacientes mediante el uso de una Historia Clínica Electrónica que incluyese tanto los datos médicos como aquellos que hacen referencia al estado psicológico y social de los mismos. Este análisis ha dado lugar al diseño y desarrollo de un sistema de telemedicina, "Hospital VIHrtual", que entre otras funciones realiza esa integración de datos, fomentando la colaboración entre los profesionales implicados en el tratamiento de los pacientes con el objetivo de mejorar el control de las personas con VIH/SIDA en estado estable y aumentar su calidad de vida

Estereótipos de Violência de Parceiro Íntimo: O Sexo e a Orientação Sexual são Importantes?

This study analyzed stereotypes on intimate partner violence (IPV) of heterosexual and same-sex couples. The participants, 232 Mexican college students, evaluated physical and psychological IPV exerted by men and women with different sexual orientations. The data were analyzed using the Wilcoxon test. The results indicate that men evaluated women and gay men as having a similar IPV, while men´s perceptions of IPV for these groups were higher than those of women. Women viewed heterosexual men as the most violent and evaluated the other groups with different degrees of IPV. Physical violence is regarded as natural in men, both gay and heterosexual. To conclude, the results suggest that IPV stereotypes are affected by the sex of the evaluators and by their sexual orientation. It is relevant to expand the scope of prevention programs.  Keywords: intimate partner violence, stereotyped attitudes, male female relations, male homosexuality, female homosexuality, MexicoEsta pesquisa avalia estereótipos sobre violência entre parceiros íntimos (VPI) relacionados a casais heterossexuais e homossexuais. Os/as participantes, 232 estudantes universitários mexicanos, avaliaram a VPI física e psicológica exercida por homens e mulheres com diferentes orientações sexuais. Os dados foram analisados com o teste de Wilcoxon. Os resultados indicam que homens avaliaram mulheres e homens gays como apresentando níveis similares de VPI, sendo a percepção masculina sobre VPI nesses grupos superior à feminina. Mulheres percebem homens heterossexuais como mais violentos e atribuem graus diferentes de VPI para os demais grupos. A violência física é vista como natural em homens, homossexuais ou heterossexuais. Para concluir, é possível sugerir que estereótipos de VPI são influenciados pelo sexo do avaliador e por sua orientação sexual. É relevante ampliar o alcance de programas preventivos

Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection in kidney transplant recipients not receiving T-cell depleting induction therapy

Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rap- idly recognize alloantigens and activate the effector immune response, which leads to allo- graft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by denovo activated na ï ve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell re- sponses were evaluated using the IFN- γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90), to assess the main clinical variables associated with cel- lular sensitization and its predominant time-frame impact on allograft outcome, and was fur- ther validated in an independent new set of kidney transplant recipients (n = 67). We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year inci- dence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular re- jection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosup- pression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensiti- zation before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction therapy

Potential of Oral Nanoparticles Containing Cytokines as Intestinal Mucosal Immunostimulants in Pigs : A Pilot Study

Antibiotics are essential compounds to cope with bacterial infections. However, their inadequate and excessive use has triggered the rapid arising of antimicrobial-resistant bacteria. In this scenario, immunostimulants, which are molecules that boost the immune system, open up a new approach to face this problem, enhancing treatment efficacy and preventing infections by immune system response. Cytokines are central effector molecules of the immune system, and their recombinant production and administration in animals could be an interesting immune modulation strategy. The aim of this study was the development of a highly stable nanoparticle of porcine cytokines to achieve the immunostimulation of intestinal mucosa in piglets. The outcomes of the present study prove this approach is able to stimulate swine intestinal cells and macrophages in vitro and tends to modulate inflammatory responses in vivo, although further studies are required to definitively evaluate their potential in animals. Antimicrobial resistance is a global threat that is worryingly rising in the livestock sector. Among the proposed strategies, immunostimulant development appears an interesting approach to increase animal resilience at critical production points. The use of nanoparticles based on cytokine aggregates, called inclusion bodies (IBs), has been demonstrated as a new source of immunostimulants in aquaculture. Aiming to go a step further, the objective of this study was to produce cytokine nanoparticles using a food-grade microorganism and to test their applicability to stimulate intestinal mucosa in swine. Four cytokines (IL-1β, IL-6, IL-8, and TNF-α) involved in inflammatory response were produced recombinantly in Lactococcus lactis in the form of protein nanoparticles (IBs). They were able to stimulate inflammatory responses in a porcine enterocyte cell line (IPEC-J2) and alveolar macrophages, maintaining high stability at low pH and high temperature. In addition, an in vivo assay was conducted involving 20 piglets housed individually as a preliminary exploration of the potential effects of IL-1β nanoparticles in piglet intestinal mucosa after a 7 d oral administration. The treated animals tended to have greater levels of TNF-α in the blood, indicating that the tested dose of nanoparticles tended to generate an inflammatory response in the animals. Whether this response is sufficient to increase animal resilience needs further evaluation