Peripheral Inflammation Enhances Microglia Response and Nigral Dopaminergic Cell Death in an in vivo MPTP Model of Parkinson’s Disease

The impact of systemic inflammation in nigral dopaminergic cell loss remains unclear. Here, we have investigated the role of peripheral inflammation induced by systemic lipopolysaccharide (LPS) administration in the MPTP-based model of Parkinson’s disease. Brain inflammation, microglia and astroglia activation, disruption of the blood–brain barrier (BBB) and integrity of the nigrostriatal dopaminergic system were evaluated in response to i.p. injection of LPS, MPTP or the combination of both. Our results showed that combinative treatment exacerbates microglia activation and enhances (i) the appearance of galectin-3-positive microglia, recently identified as microglial disease-associated phenotypic marker, (ii) the up-regulation of pro-inflammatory cytokines, (iii) the occurrence of A1 neurotoxic astrocytes, (iv) the breakdown of the BBB, and (v) the loss of dopaminergic neurons in the substantia nigra. Microglia activation was triggered earlier than other degenerative events, suggesting that over-activation of microglia (including different polarization states) may induce dopaminergic neuron loss by itself, initiating the endless cycle of inflammation/degeneration. Our study revitalizes the importance of peripheral inflammation as a potential risk factor for Parkinson’s disease and raises the possibility of using new anti-inflammatory therapies to improve the course of neurodegenerative diseases, including those directly aimed at modulating the deleterious activity of disease-associated microglia.España MINECO y FEDER SAF2015-64171-

CD44-negative parietal–epithelial cell staining in minimal change disease: association with clinical features, response to corticosteroids and kidney outcome

Idiopathic nephrotic syndrome; Minimal change disease; Parietal–epithelial cellsSíndrome nefrótico idiopático; Enfermedad de cambios mínimos; Células parietales-epitelialesSíndrome nefròtica idiopàtica; Malaltia de canvis mínims; Cèl·lules parietals-epitelialsBackground Activation of parietal–epithelial cells (PECs) with neo-expression of CD44 has been found to play a relevant role in the development of focal and segmental glomerulosclerosis (FSGS). The aim of this study was to analyse whether the expression of CD44 by PECs in biopsies of minimal change disease (MCD) is associated with the response to corticosteroids, with kidney outcomes and/or can be considered an early sign of FSGS. Methods This multicentric, retrospective study included paediatric and adult patients with MCD. Demographic, clinical and biochemical data were recorded, and biopsies were stained with anti-CD44 antibodies. The association between PECs, CD44 expression and the response to corticosteroids, and kidney outcomes were analysed using logistic, Kaplan–Meier and Cox regression analyses. Results A total of 54 patients were included: 35 (65%) <18 years and 19 (35%) adults. Mean follow-up was 68.3 ± 37.9 months. A total of 19/54 patients (35.2%) showed CD44-positive staining. CD44-positive patients were younger (14.5 ± 5 versus 21.5 ± 13, P = 0.006), and showed a higher incidence of steroid-resistance [11/19 (57.8%) versus 7/35 (20%), P = 0.021; odds ratio: 5.5 (95% confidence interval 1.6–18), P = 0.007] and chronic kidney disease [9/19 (47.3%) versus 6/35 (17.1%), P = 0.021; relative risk: 3.01 (95% confidence interval 1.07–8.5), P = 0.037]. Follow-up re-biopsies of native kidneys (n = 18), identified FSGS lesions in 10/12 (83.3%) of first-biopsy CD44-positive patients versus 1/6 (16.7%) of first-biopsy CD44-negative patients (P = 0.026). Conclusions In patients with a light microscopy pattern of MCD, CD44-positive staining of PECs is associated with a higher prevalence of steroid resistance and worse kidney outcomes, and can be considered an early sign of FSGS.C.M. is supported by a Miguel Servet grant, Fondo de investigación sanitaria, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovacio´n y Universidades [CP18/00116]. No additional funding was required for the current study

Matrices de probabilidad de daño para la catedral de Mallorca, España

Se presenta la obtención de la vulnerabilidad sísmica para una catedral Gótica de grandes dimensiones mediante la aplicación del Método del Espectro de Capacidad, y la obtención de las probabilidades de daño asociadas.Peer ReviewedPostprint (published version

Effects of the COVID-19 Health Crisis on Sports Practice, Life Quality, and Emotional Status in Spanish High-Performance Athletes

Ajuts: This work belongs to the "Efectos de la nueva normalidad por crisis sanitaria COVID-19 en la práctica deportiva, la calidad de vida y el estado emocional de los deportistas de élite en España, EASED (CoV-19)" project, supported by San Antonio Catholic University (UCAM) (Plan Propio, PMAFICOVID19/19), Murcia, Spain.Spain is one of the many countries highly affected by the COVID-19 crisis, establishing very restrictive measures with a complete lockdown for more than 3 months. This situation forced the complete closure of sport practice and national or international competitions, leading to a negative impact on physical and psychological health of high-performance athletes. Therefore, the objectives of this study were (a) to determine the effects of the COVID-19 health crisis on Spanish high-performance athletes in terms of sports practice, life quality, and emotional state and (b) to identify the profile with the greatest difficulties during and after the lockdown. A sample of 130 high-performance athletes aged between 18 and 34 years (67 women and 63 men) participated in this study (83.1% achieved a medal in National-International elite competitions; 86.9% were considered student-athletes). Measures included socio-demographic data through a 5-dimension ad hoc survey: physical activity and exercise using an adapted version from the International Physical Activity Questionnaire (IPAQ) ; health status and limitations using an adapted version of SF-12 Health Questionnaire ; Perceived stress (Short-PSS) ; and Mood States (29-item POMS). All participants have shown a significant decrease pre-post-lockdown in both health and performance perception, especially in women, individual athletes, medalists, and student-athletes. Strong limitations of training, attention, and motivation as well as a moderate negative emotional state during lockdown were reported, in women, individual athletes, medalists, and student-athletes. Even with an improved emotional state and energy level in the post-lockdown period, moderate-to-high stress scores were reported by women and medalists. Our findings highlight the importance of paying attention to the physical and psychological health of elite athletes on three profiles: team athletes (due to social distance), student-athletes (dual-career issues), and women athletes (prevalence of implicit gender inequalities in sport)

Insights into interface and bulk defects in a high efficiency kesterite-based device

This work provides a detailed analysis of a high efficiency Cu2ZnSnSe4 device using a combination of advanced electron microscopy and spectroscopy techniques. In particular, a full picture of the different defects present at the interfaces of the device and in the bulk of the absorber is achieved through the combination of high resolution electron microscopy techniques with Raman, X-ray fluorescence and Auger spectroscopy measurements at the macro, micro and nano scales. The simultaneous investigation of the bulk and the interfaces allows assessing the impact of the defects found in each part of the device on its performance. Despite a good crystalline quality and homogeneous composition in the bulk, this work reports, for the first time, direct evidence of twinning defects in the bulk, of micro and nano-voids at the back interface and of grain-to-grain non-uniformities and dislocation defects at the front interface. These, together with other issues observed such as strong absorber thickness variations and a bilayer structure with small grains at the bottom, are shown to be the main factors limiting the performance of CZTSe devices. These results open the way to the identification of new solutions to further developing the kesterite technology and pushing it towards higher performances. Moreover, this study provides an example of how the advanced characterization of emergent multilayer-based devices can be employed to elucidate their main limitations.Peer ReviewedPostprint (author's final draft

Melatonin receptors MT1 and MT2 are expressed in spermatozoa from several seasonal and nonseasonal breeder species

P. 1958-1968Melatonin is a ubiquitous and multipurpose molecule, and one of its roles is to regulate reproduction in some seasonal mammals. Our group has previously reported the variation in the melatonin levels in ram seminal plasma along the year and identified MT1 and MT2 receptors in ram spermatozoa. The objective of this study was to elucidate whether the presence of melatonin receptors (MT1 and MT2) in the sperm plasma membrane, and melatonin in the seminal plasma is related to seasonal breeding. For this purpose, the presence of melatonin receptors and the levels of melatonin in seminal plasma have been examined in several species: donkey and stallion as long-day breeders; red deer as a wild, short-day, highly seasonal breeder (epididymal spermatozoa); bull as a conventional nonseasonal breeder; boar as a seasonal breeder under management techniques; and dog as possible a seasonal breeder not regulated by melatonin. We have detected measurable levels of melatonin in the seminal plasma of all ejaculated semen samples (from donkey, stallion, boar, bull, and dog). Also, and for the first time, we have demonstrated the presence of MT1 and MT2 melatonin receptors in the spermatozoa of all these species, regardless their type of reproduction or sperm source (ejaculated or epididymal), using indirect immunofluorescence techniques and Western blotting. Our findings suggest that melatonin and melatonin receptors may be universally distributed in the reproductive system of mammals and that the sperm melatonin receptors cells may not be necessarily related with seasonal reproduction. Furthermore, the presence of MT1 at the cytoplasmic droplet in immature ejaculated stallion spermatozoa found in one sample and epididymal red deer spermatozoa suggests that melatonin may be involved in specific functions during spermatogenesis and sperm maturation, like protecting spermatozoa from oxidative damage, this activity being mediated through these receptors.S

Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis

Background: Sepsis, a life-threatening organ dysfunction caused by a dysregulated systemic immune response to infection, associates with reduced responsiveness to subsequent infections. How such tolerance is acquired is not well understood but is known to involve epigenetic and transcriptional dysregulation. Methods: Bead arrays were used to compare global DNA methylation changes in patients with sepsis, noninfectious systemic inflammatory response syndrome, and healthy controls. Bioinformatic analyses were performed to dissect functional reprogramming and signaling pathways related to the acquisition of these specific DNA methylation alterations. Finally, in vitro experiments using human monocytes were performed to test the induction of similar DNA methylation reprogramming. Results: Here, we focused on DNA methylation changes associated with sepsis, given their potential role in stabilizing altered phenotypes. Tolerized monocytes from patients with sepsis display changes in their DNA methylomes with respect to those from healthy controls, affecting critical monocyte-related genes. DNA methylation profiles correlate with IL-10 and IL-6 levels, significantly increased in monocytes in sepsis, as well as with the Sequential Organ Failure Assessment score; the observed changes associate with TFs and pathways downstream to toll-like receptors and inflammatory cytokines. In fact, in vitro stimulation of toll-like receptors in monocytes results in similar gains and losses of methylation together with the acquisition of tolerance. Conclusion: We have identified a DNA methylation signature associated with sepsis that is downstream to the response of monocytes to inflammatory signals associated with the acquisition of a tolerized phenotype and organic dysfunction

Increased Th17-Related Cytokine Serum Levels in Patients With Multiple Polyps of Unexplained Origin

OBJECTIVES: Most patientswith multiple colonic polyps do not have a known genetic or hereditary origin. Our aim was to analyze the presence of inflammatory cytokines and levels of glucose, insulin, and C-reactive protein (CRP) in patients with multiple colonic polyps. METHODS: Eighty-three patients with 10 or more adenomatous or serrated polyps and 53 control people with normal colonoscopy were included. Smoking habits were registered, and glucose, CRP, and basal insulin in the serum/blood weremeasured. Quantification of IL-2, IL-4, IL-6, IL-10, IL-11, IL-17A, and IL-23 cytokine levels in the serum was performed by a high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Smoking and diabetesweremore prevalent in those with colonic polyps than in the control people (67% vs 16%, P = 0.001; 11% vs 2%, P = 0.048). In addition, the cytokine serum levels were higher, i.e., IL-2 (P = 0.001), IL-4 (P = 0.001), IL-6 (P = 0.001), IL-17A (P = 0.001), IL-23 (P = 0.014), and CRP (P = 0.003). Adjusting for sex, smoking, and diabetes in amultivariate analysis, IL-2, IL-4, IL-6, IL-17A, and IL-23 remained independently elevated in cases with multiple polyps. DISCUSSION: These results indicate that immune responses mediated by Th17 cells may be involved in the pathogenesis of multiple colonic polyps

Impact of introducing assisted electronic prescription on paediatric patient safety

[Resumen] Objetivo. El efecto de la implantación de la prescripción electrónica asistida en la seguridad de los pacientes pediátricos ha sido poco estudiado. El objetivo de este estudio es comparar los errores de medicación antes y después de su implantación en un hospital terciario. Material y métodos. Estudio cuasiexperimental comparativo de los errores de medicación detectados antes y después de la implantación de la prescripción electrónica. Se analizaron todas las líneas de tratamiento y se recogió el punto de la cadena donde ocurrió el error, el tipo de error y su causa. Se realizó un estudio Delphi sobre la importancia de cada error en el que participaron médicos, enfermeros y farmacéuticos. Resultados. Se incluyeron 166 pacientes (83 en cada etapa). Se detectó algún error en el 92% de los pacientes en la etapa preimplantacional (2,8 ± 2,1 errores/paciente) y en el 7,2% en la etapa postimplantacional (0,1 ± 0,4 errores/paciente). La prescripción electrónica asistida supuso una reducción absoluta del riesgo de error de un 40% (intervalo de confianza del 95% = 35,6-44,4%). Los lapsus/despistes fueron la principal causa de error en ambos grupos. En la etapa preimplantacional se consideraron graves el 9,5% de los errores, y en la etapa postimplantacional todos fueron leves o moderados. Conclusiones. La implantación de la prescripción electrónica con sistemas de ayuda a la prescripción, validación y administración de medicamentos reduce de forma significativa los errores de medicación y elimina los errores graves.[Abstract] Objective. There have been very few studies on the effect of assisted electronic prescription on paediatric patient safety. The objective of this study is to compare medication errors that occurred before and after its introduction in a tertiary hospital. Material and methods. A quasi-experimental comparative study of medication errors detected before and after assisted electronic prescription introduction. All treatment lines were analysed in order to detect the point in the chain where the medication error occurred, as well as its type and cause. A Delphi study was conducted on the importance of each medication error involving doctors, nurses, and pharmacists. Results. The study included 166 patients (83 at each stage). At least one medication error was detected in 92% in the pre-introduction phase patients (2.8 ± 2.1 errors/patient) and 7.2% of post-introduction phase patients (0.1 ± 0.4 errors/patient). The assisted electronic prescription led to an absolute risk reduction of 40% (95% confidence interval = 35.6-44.4%). The main cause of error was lapses and carelessness in both stages. Medication errors were considered serious in 9.5% of cases in the pre-introduction phase, while all of them were mild or moderate in the post-introduction phase. Conclusions. The assisted electronic prescription implementation with prescription, validation and medication administration assistance systems significantly reduces medication errors and eliminates serious errors

Efficacy and safety of a booster dose of influenza vaccination in solid organ transplant recipients, TRANSGRIPE 1-2: study protocol for a multicenter, randomized, controlled clinical trial

BACKGROUND: Despite administration of annual influenza vaccination, influenza-associated complications in transplant recipients continue to be an important cause of hospitalization and death. Although influenza vaccination has been proven to be the most effective measure to reduce influenza infection after transplantation, transplant recipients are still vulnerable to influenza infections, with lower serological responses to vaccination compared to the general population. In order to assess the efficacy and safety of an alternative immunization scheme for solid organ transplant recipients, the TRANSGRIPE1-2 Study Group aimed to test a booster dose administration 5 weeks after the standard vaccination. The primary objective of this trial was to compare short-term and long-term neutralizing antibody immunogenicity of a booster dose of influenza vaccination to the standard single-dose immunization scheme. Secondary objectives included the evaluation of the efficacy and/or safety, cellular immune response, incidence of influenza infection, graft rejection, retransplant and mortality rates. METHODS/DESIGN: This phase III, randomized, controlled, open-label clinical trial was conducted between October 2012 and December 2013 in 12 Spanish public referral hospitals. Solid organ transplant recipients (liver, kidney, heart or lung), older than 16 years of age more than 30 days after transplantation were eligible to participate. Patients (N = 514) were stratified 1:1 by center, type of organ and time after transplantation and who either received the standard single dose (n = 257) or were treated according to a novel influenza vaccination schedule comprising the administration of a booster dose 5 weeks after standard vaccination (n = 254). Seroconversion rates were measured as a determinant of protection against influenza (main outcome). Efficacy and safety outcomes were followed until 1 year after influenza vaccination with assessment of short-term (0, 5, 10 and 15 weeks) and long-term (12 months) results. Intention-to-treat, per-protocol and safety analyses will be performed. DISCUSSION: This trial will increase knowledge about the safety and efficacy of a booster dose of influenza vaccine in solid organ transplant recipients. At the time the manuscript was submitted for publication, trial recruitment was closed with a total of 499 participants included during a 2-month period (within the seasonal influenza vaccination campaign). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01761435 (registered 13 December 2012). EudraCT Identifier: 2011-003243-21 (registered 4 July 2011)