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Inflammation is a predominant aspect of neurodegenerative diseases, manifested by glia activation and expression of pro-inflammatory mediators. Studies on animal models of Parkinson’s disease (PD) suggest that sustained neuroinflammation exacerbates degeneration of the dopaminergic (DA) nigro-striatal pathway. Therefore, insights into the inflammatory mechanisms of PD may help the development of novel therapeutic strategies against this disease. As extracellular matrix metalloproteinases (MMPs) could be major players in the progression of Parkinsonism, we investigated, in the substantia nigra and striatum of mice acutely injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), changes in mRNA expression, protein levels, and cell localization of MMP-9. This protease is mainly neuronal, but early after MPTP injection its mRNA and protein levels, as well as the number of MMP-9-expressing microglia and astrocytes, increase concomitantly to a prominent inflammation. Neuroinflammation and MMP-9 + glia begin to decline within 2 weeks, although protein levels remain higher than control, in association with a partial recovery of DA nigro-striatal circuit. Comparable quantitative studies on MMP-9 knock-out mice, show a significant decrease in both glia activation and loss of DA neurons and fibers, with respect to wild-type. Moreover, in a parallel study on chronically MPTP-injected macaques, we observed that perpetuation of inflammation and high levels of MMP-9 are associated to DA neuron loss. Our data suggest that MMP-9 released by injured neurons favors glia activation; glial cells in turn reinforce their reactive state via autocrine MMP-9 release, contributing to nigro-striatal pathway degeneration. Specific modulation of MMP-9 activity may, therefore, be a strategy to ameliorate harmful inflammatory outcomes in Parkinsonism.

To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN- γ and TNF- α in experimental models of Parkinson's disease and analyze their relation with local glial cell activation. It was found that IFN- γ and TNF- α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta . Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN- γ R signaling in both microglial and astroglial cells. In addition, experiments performed in IFN- γ and TNF- α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN- γ and TNF- α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN- γ signaling, together with the contribution of TNF- α , have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism.

To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-γ and TNF-α in experimental models of Parkinson’s disease and analyze their relation with local glial cell activation. It was found that IFN-γ and TNF-α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-γR signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-γ and TNF-α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-γ and TNF-α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-γ signaling, together with the contribution of TNF-α, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism.

Correction to: Cell Death and Disease (2011) 2, e142; doi: 10.1038/cddis.2011.17; published online 7 April 2011 Since the publication of this article an error has been identified in one of the authors names. D Aguado-Yera should have been D Aguado-Llera. The correct list is shown above. The authors would like to apologize for any confusion this may have caused.

To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-γ and TNF-α in experimental models of Parkinson's disease and analyze their relation with local glial cell activation. It was found that IFN-γ and TNF-α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-γR signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-γ and TNF-α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-γ and TNF-α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-γ signaling, together with the contribution of TNF-α, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism.

Background:Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease characterized by diarthrodial joint damage. Currently, there is no consensus on how to treat a patient in sustained remission. There are still questions about whether we should consider dose de-escalation strategies or should continue with standard therapy. Based in that, discovery of a model to predict flares or remission in RA patients in clinical remission is justified.Objectives:To evaluate, in patients with RA in clinical remission and under biological therapy, the proportion of patients who, at the end of the 1st, 2nd and 3rd year with treatment, remain in remission or have a joint flare with a strategy of gradual tapering of biological therapy in comparison to patients receiving standard treatment. Determine which variables act as a risk factor for the development of joint flares and develop a flare prediction model of disease activity.Methods:Patients were selected from the OPTIBIO protocol (Eudra-CT code 2012-004482-40) and from the REMRABIT Project (PMP15/00032). Experimental Design: Multicenter, open-label, randomized, controlled, phase IV clinical trial comparing two treatment strategies in patients with RA in remission. Patients over 18 years of age with RA who met the 1987 ACR classification criteria and who were in remission for 6 months and on biologic therapy (TNFi and Tocilizumab) were included. Clinical-demographic variables, indices of disease activity, and serological markers were collected. Two treatment regimens were compared, a control group that continued treatment according to the drug label and an optimization group in which a standardized protocol of drug dose reduction was used. A descriptive analysis of baseline characteristics was performed in each arm. The quantitative variables were expressed as mean and standard deviation and the qualitative variables as absolute and relative frequencies. The comparison of means between treatment arms was carried out using the Student’s T test or Mann-Whitney U test as appropriate after normality analysis (Kolmogorov-Smirnov Test). For the association between qualitative variables, Pearson’s chi-square test or Fisher’s exact test was used. Cox regression models were used to study the factors associated with the appearance of flare in each arm. The Kaplan-Meier method was used to estimate flare-free survival. The comparison between survival curves was analyzed using the Log-Rank test. The statistical software SPSS v28 and R v.4.3.1 were used.Results:A total of 196 patients were included, 99 in the control group and 96 in the optimization group. There was no statistical significance between the variables analyzed in both groups, so we determined a homogeneous sample.The flares in the 1st, 2nd and 3rd year were: 16 (53.3%), 12 (40%) and 2 (7%) in the control group and 24 (53.3%), 20 (44.4%) and 1 (2%) in the optimization group, respectively. Only the comparison of total flares in both arms were statistically significant, control group 30 (40%) vs optimization 45 (60%) p=0.02.However, the flare-free survival curve at 18 and 24 months showed statistic difference between bout groups (Figure 1). The variables associated with flare were in the control group: ESR, CRP, DAS28, DAS28-ESR, DAS28-CRP, DAS28 (3V-PCR) and HAQ and in the optimization group: BMI, CRP, DAS28, DAS28-CRP, DAS28 (3V-PCR), DAS28 (3V-ESR), SDAI and HAQ (Table 1).The best flare prediction model has an AUC of 0,75, sensitivity of 70% and specificity of 77%.Conclusion:The dose-reduction strategy of biologic therapy in patients with RA in remission used in this study was associated with increased risk of disease activity flare at 18 months. From all variables analyzed, CRP, DAS28-CRP, and a higher HAQ were associated with increased risk of flare in both groups. In this study we have developed a predictive model of joint flare that may be useful for using personalized medicine in RA. Inclusion of molecular data (genetic and proteomic biomarkers) could improve the prediction of this clinical model.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Francisco J. Blanco funding from Gedeon Richter Plc., Bristol-Myers Squibb International Corporation (BMSIC), Sun Pharma Global FZE, Celgene Corporation, Janssen Cilag International N.V, Janssen Research & Development, Viela Bio, Inc., Astrazeneca AB, UCB BIOSCIENCES GMBH, UCB BIOPHARMA SPRL, AbbVie Deutschland GmbH & Co.KG, Merck KGaA, Amgen, Inc., Novartis Farmacéutica, S.A., Boehringer Ingelheim España, S.A, CSL Behring, LLC, Glaxosmithkline Research & Development Limited, Pfizer Inc, Lilly S.A., Corbus Pharmaceuticals Inc., Biohope Scientific Solutions for Human Health S.L., Centrexion Therapeutics Corp., Sanofi, TEDEC-MEIJI FARMA S.A., KiniksaPharmaceuticals, Ltd. Grunenthal, Laura Galindo: None declared, Belen Acasuso: None declared, Vanesa Balboa-Barreiro: None declared, Juan Fernández-Tajes: None declared, Juan de Dios Cañete Crespillo: None declared, Benjamin Fernández-Gutiérrez: None declared, Isidoro González-Álvaro: None declared, José Luis Pablos Álvarez: None declared, Carmen Bejerano: None declared, Maite Silva: None declared, Francisco Javier de-Toro-Santos: None declared, Natividad Oreiro: None declared.

Parker Solar Probe observations show ubiquitous magnetic-field reversals closer to the Sun, often referred to as “switchbacks”. The switchbacks have been observed before in the solar wind near 1 AU and beyond, but their occurrence was historically rare. PSP measurements below ∼ 0.2 AU show that switchbacks are, however, the most prominent structures in the “young” solar wind. In this work, we analyze remote-sensing observations of a small equatorial coronal hole to which PSP was connected during the perihelion of Encounter 1. We investigate whether some of the switchbacks captured during the encounter were of coronal origin by correlating common switchback in situ signatures with remote observations of their expected coronal footpoint. We find strong evidence that timescales present in the corona are relevant to the outflowing, switchback-filled solar wind, as illustrated by strong linear correlation. We also determine that spatial analysis of the observed region is optimal, as the implied average solar-wind speed more closely matches that observed by PSP at the time. We observe that hemispherical structures are strongly correlated with the radial proton velocity and the mass flux in the solar wind. The above findings suggest that a subpopulation of the switchbacks are seeded at the corona and travel into interplanetary space.

Introduction/Background*Ovarian cancer (OC) is the most lethal gynaecological malignancy worldwide The standard management of ovarian cancer in premenopausal women is not clear, and much controversy remains as to whether within this group of patients some of them with advanced stages should have primary cytoreductive surgery followed by chemotherapy or neoadjuvant chemotherapy followed by interval cytoreductive surgery. There is increasing evidence that the patients gain the most benefit from surgery are those with no residual disease at the completion of surgery (R0 resection).MethodologyRetrospective analysis of women under 45 years old diagnosed of epithelial and non-epithelial ovarian cancer during the last 10 years.Result(s)*25 women under 45 years with OC were reviewed. Mean age at diagnosis was 36.27 years (SD 5.77; min:21, max: 43). Most of the tumors (52% N:13) were epithelial serous OC (Clear cells: 20.0% N:5; Endometrioid: 12.0 N:3; Mucinous: 8.0% N:2; Endodermal sinus: 4.0% N:1; Granulosa cell: 4.0% N: 1). Most of the patients were diagnosed in advanced tumoral stages (III-IV: 68.0%, N:17). Only 7 patients received neadyuvant quemotherapy (28%) previous to surgery. Surgical cytoreduction was made by laparotomy in most cases (84.0% N:21) preferred to laparoscopy (N:4, 16.0%). Complete surgical cytoreduction was achieved in 82.0% of cases (N:19). Surgical approach included: bilateral oophorectomy (96.0%, N:24), hysterectomy (82.0% N:19), omentectomy (96% N:24), appendicectomy (60.0% N:15), peritoneal biopsy (92.0% N: 23), peritonectomy (60.0% N:15), liver resection (40.0% N:10), intestinal resection (32.0% N:8), splenectomy (N:4), colecistectomy (N:2). Pelvic and paraaortic linfadenectomy was performed in 56.0% of cases (N: 14). Mean time of hospitalization was 7.84 days (4.16 SD; max:15, min:1). Few patients had complications: surgical urologic complications: 12.0% N:3; postsurgery complications: urological (N:2), abdominal wall infection (N:2), eventration (N:1), vascular (N:1).Conclusion*Ovarian cancer in premenopausal women is a threatening condition, diagnosed in most cases in advanced stages, that needs a combination of quemotherapy and surgery. Surgical approach must be aggressive in order to achieve a complete resection of the tumor.

Background Acute kidney injury (AKI) is a significant postoperative complication associated with increased mortality and hospital costs. Hemodynamic strategies, such as goal-directed therapy, might reduce AKI risk. Predicting and proactively managing intraoperative hypotension may be helpful. This trial aims to investigate if a preemptive hemodynamic strategy guided by the hypotension prediction index (HPI) can decrease the incidence of moderate-to-severe AKI within 30 days following major elective abdominal surgery. Methods This is an open-label, controlled, multicenter, randomized clinical trial that involves daily patient follow-up until hospital discharge. Inclusion criteria are patients aged over 65 and/or categorized as ASA III or IV physical status, undergoing major elective abdominal surgery (general, urological, or gynecological procedures) via laparoscopic or open approach under general or combined anesthesia. Intervention In the intervention group, hemodynamic management will be based on the HPI and the advanced functional hemodynamic variables provided by the Hemosphere platform and the AcumenIQ® sensor (Edwards Lifesciences). The primary outcome is the incidence of moderate-to-severe AKI within 7 days post-surgery. Secondary outcomes include postoperative complications and 30-day mortality. Discussion This study explores the potential of HPI-guided hemodynamic management in reducing AKI after major elective abdominal surgery, with implications for postoperative outcomes and patient care. Trial registration ClinicalTrials.gov NCT05569265. Registered on October 6, 2022.