Polysialylated neuropilin-2 enhances human dendritic cell migration through the basic C-terminal region of CCL21.

Free Access at: http://glycob.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=20488940Dendritic cell (DC) migration to secondary lymphoid organs is a critical step to properly exert its role in immunity; and predominantly depends on the interaction of the chemokine receptor CCR7 with its ligands CCL21 and CCL19. Polysialic acid (PSA) has been recently reported to control CCL21-directed migration of mature DCs. Here; we first demonstrate that PSA present on human mature monocyte-derived dendritic cells did not enhance chemotactic responses to CCL19. We have also explored the molecular mechanisms underlying the selective enhancing effect of PSA on CCL21-driven chemotaxis of DCs. In this regard; we found out that prevention of DC polysialylation decreased CCL21 activation of JNK and Akt signaling pathways; both associated with CCR7-mediated chemotaxis. We also report that the enhanced PSA-mediated effect on DC migration towards CCL21 relied on the highly basic C-terminal region of this chemokine; and depended on the PSA acceptor molecule neuropilin-2 (NRP2) and on the polysialyltransferase ST8SiaIV. Altogether; our data indicate that the CCR7/CCL21/NRP2/ST8SiaIV functional axis constitutes an important guidance clue for DC targeting to lymphoid organs.This work was supported by research grant from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (FISPI0708879 to MAV).Peer reviewe

Endodontic regenerative treatment for internal radicular resorption using bio-ceramic material, case report

The internal resorption of the internal radicular conduct is a process than can be both physiological or pathological, being the osteoclasts, odontoclasts and dentinoclast responsible for said process. 49-year-old female patient, refers orthodontic treatment at age 20, attends a dental check-up due to pain when chewing. Dental organ (DO) #11 was diagnosed with internal root resorption and symptomatic, suppurative apical periodontitis. Treatment started performing an endodontic access and taking a conductometry reading with an apical foramen locator, using a precision hybrid instrumentation technique and applying hypochlorite irrigation, the intra-canal was medicated with chemically pure calcium hydroxide for 7 days. The canal obturation was repaired infiltrating a bio-ceramic material (BIO-C Sealer) followed by the placement of the single cone using a vertical condensation technique

Activation of LXR nuclear receptors impairs the anti-inflammatory gene and functional profile of M-CSF-dependent human monocyte-derived macrophages

13 p.-7 fig.Liver X Receptors (LXR) control cholesterol metabolism and exert anti-inflammatory actions but their contribution to human macrophage polarization remains unclear. The LXR pathway is enriched in pro-inflammatory macrophages from rheumatoid arthritis as well as in tumors-associated macrophages from human tumors. We now report that LXR activation inhibits the anti-inflammatory gene and functional profile of M-CSF-dependent human macrophages, and prompts the acquisition of a pro-inflammatory gene signature, with both effects being blocked by an LXR inverse agonist. Mechanistically, the LXR-stimulated macrophage polarization shift correlates with diminished expression of MAFB and MAF, which govern the macrophage anti-inflammatory profile, and with enhanced release of activin A. Indeed, LXR activation impaired macrophage polarization in response to tumor-derived ascitic fluids, as well as the expression of MAF- and MAFB-dependent genes. Our results demonstrate that LXR activation limits the anti-inflammatory human macrophage polarization and prompts the acquisition of an inflammatory transcriptional and functional profile.This work was supported by grants from Ministerio de Ciencia, Investigación y Universidades (SAF2017-83785-R to MV and ALC), Ministerio de Ciencia, Innovación y Universidades y Fondo Europeo de Desarrollo Regional (FEDER) (SAF2017-90604-REDT and PID2019-104284RB-I00/AEI/10.13039/501100011033 to AC), Fundación La Marató/TV3 (Grant 201619.31 to ALC), Instituto de Salud Carlos III (Grant PI20/00316 to AP-K), and Red de Investigación en Enfermedades Reumáticas (RIER, RD16/0012/0007) from Instituto de Salud Carlos III and cofinanced by the European Regional Development Fund “A way to achieve Europe” (ERDF) to AP-K and ALC. This work was also supported in part by a grant from the Dutch Society for Clinical Chemistry (NVKC) to IM and R. de Jonge. AGA was funded by FPU predoctoral fellowship (FPU16/02756) from Ministerio de Universidades.Peer reviewe

The GSK3b-MAFB axis controls the pro-fibrotic gene profile of pathogenic monocyte-derived macrophages in severe COVID-19

1 p.-4 fig.MAF and MAFB are members of the “large MAF” transcription factor family that shape the transcriptome of antiinflammatory and pro-tumoral human macrophages. We have now determined the MAF- and MAFB-dependent gene profile of M-CSF-dependent monocyte-derived macrophages (M-MØ), and found that both factors exhibit overlapping transcriptional outcomes during monocyte-to-M-MØ differentiation, but differentially affect macrophage effector functions like production of monocyte-recruiting chemokines, T-cell activation and immunosuppression. Remarkably, MAFB was found to positively regulate the expression of the genesets that define the pathogenic monocyte-derived pulmonary macrophage subsets in COVID-19, as evidenced through siRNA-mediated silencing and analysis of MAFBoverexpressing M-MØ from a Multicentric Carpotarsal Osteolysis (MCTO) patient. MAFB silencing downregulated theexpression of genes coding for biomarkers of COVID-19 severity, and genome-wide mapping of MAFB-binding elements in M-MØ identified biomarkers of COVID-19 severity (CD163, IL10, HGF and CCL2) as direct MAFB targets. Further, and in line with the GSK3b-dependent expression of MAFB, GSK3b inhibition in M-MØ significantly boosted the expression of genes that characterize pathogenic macrophage subsets in severe COVID-19, an effect that was primarily dependent on MAFB. In addition, we have demonstrated that a large number of MAFB-dependent genes, as well as GSK3b-dependent expression of MAFB genes were modulated by SARS-Cov-2 infection on human macrophages. Globally, our results demonstrate that the GSK3b-MAFB axis controls the transcriptome of pathogenic pulmonary macrophages in COVID-19,and positively regulates the expression of biomarkers for COVID-19 severity. Thus, macrophage re-programming through modulation of GSK3 -MAFB axis has potential therapeutic strategy for COVID-19 and other inflammatory diseases.This research work was also funded by the European Commission– NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global).Peer reviewe

Relationship between olive oil consumption and ankle-brachial pressure index in a population at high cardiovascular risk

The aim of this study was to ascertain the association between the consumption of different categories of edible olive oils (virgin olive oils and olive oil) and olive pomace oil and ankle-brachial pressure index (ABI) in participants in the PREDIMED-Plus study, a trial of lifestyle modification for weight and cardiovascular event reduction in individuals with overweight/obesity harboring the metabolic syndrome. Methods: We performed a cross-sectional analysis of the PREDIMED-Plus trial. Consumption of any category of olive oil and olive pomace oil was assessed through a validated food-frequency questionnaire. Multivariable linear regression models were fitted to assess associations between olive oil consumption and ABI. Additionally, ABI ≤1 was considered as the outcome in logistic models with different categories of olive oil and olive pomace oil as exposure. Results: Among 4330 participants, the highest quintile of total olive oil consumption (sum of all categories of olive oil and olive pomace oil) was associated with higher mean values of ABI (beta coefficient: 0.014, 95% confidence interval [CI]: 0.002, 0.027) (p for trend = 0.010). Logistic models comparing the consumption of different categories of olive oils, olive pomace oil and ABI ≤1 values revealed an inverse association between virgin olive oils consumption and the likelihood of a low ABI (odds ratio [OR] 0.73, 95% CI [0.56, 0.97]), while consumption of olive pomace oil was positively associated with a low ABI (OR 1.22 95% CI [1.00, 1.48]). Conclusions: In a Mediterranean population at high cardiovascular risk, total olive oil consumption was associated with a higher mean ABI. These results suggest that olive oil consumption may be beneficial for peripheral artery disease prevention, but longitudinal studies are needed

Integrative development of a short screening questionnaire of highly processed food consumption (sQ-HPF)

Background: Recent lifestyle changes include increased consumption of highly processed foods (HPF), which has been associated with an increased risk of non-communicable diseases (NCDs). However, nutritional information relies on the estimation of HPF consumption from food-frequency questionnaires (FFQ) that are not explicitly developed for this purpose. We aimed to develop a short screening questionnaire of HPF consumption (sQ-HPF) that integrates criteria from the existing food classification systems. Methods: Data from 4400 participants (48.1% female and 51.9% male, 64.9 +/- 4.9 years) of the Spanish PREDIMED-Plus (PREvention with MEDiterranean DIet) trial were used for this analysis. Items from the FFQ were classified according to four main food processing-based classification systems (NOVA, IARC, IFIC and UNC). Participants were classified into tertiles of HPF consumption according to each system. Using binomial logistic regression, food groups associated with agreement in the highest tertile for at least two classification systems were chosen as items for the questionnaire. ROC analysis was used to determine cut-off points for the frequency of consumption of each item, from which a score was calculated. Internal consistency of the questionnaire was assessed through exploratory factor analysis (EFA) and Cronbach's analysis, and agreement with the four classifications was assessed with weighted kappa coefficients. Results: Regression analysis identified 14 food groups (items) associated with high HPF consumption for at least two classification systems. EFA showed that items were representative contributors of a single underlying factor, the HPF dietary pattern (factor loadings around 0.2). We constructed a questionnaire asking about the frequency of consumption of those items. The threshold frequency of consumption was selected using ROC analysis. Comparison of the four classification systems and the sQ-HPF showed a fair to high agreement. Significant changes in lifestyle characteristics were detected across tertiles of the sQ-HPF score. Longitudinal changes in HPF consumption were also detected by the sQ-HPF, concordantly with existing classification systems. Conclusions: We developed a practical tool to measure HPF consumption, the sQ-HPF. This may be a valuable instrument to study its relationship with NCDs

Effect of a nutritional intervention based on an energy-reduced Mediterranean diet on environmental impact

[EN]To estimate the environmental impact of a dietary intervention based on an energy-reduced Mediterranean diet (MedDiet) after one year of follow-up. Methods Baseline and 1-year follow-up data were used for 5800 participants aged 55–75 years with metabolic syndrome in the PREDIMED-Plus study. Food intake was estimated through a validated semiquantitative food consumption frequency questionnaire, and adherence to the MedDiet was estimated through the Diet Score. Using the EAT-Lancet Commission tables we assessed the influence of dietary intake on environmental impact (through five indicators: greenhouse gas emissions (GHG), land use, energy used, acidification and potential eutrophication). Using multivariable linear regression models, the association between the intervention and changes in each of the environmental factors was assessed. Mediation analyses were carried out to estimate to what extent changes in each of 2 components of the intervention, namely adherence to the MedDiet and caloric reduction, were responsible for the observed reductions in environmental impact. Results We observed a significant reduction in the intervention group compared to the control group in acidification levels (−13.3 vs. -9.9 g SO2-eq), eutrophication (−5.4 vs. -4.0 g PO4-eq) and land use (−2.7 vs. -1.8 m2). Adherence to the MedDiet partially mediated the association between intervention and reduction of acidification by 15 %, eutrophication by 10 % and land use by 10 %. Caloric reduction partially mediated the association with the same factors by 55 %, 51 % and 38 % respectively. In addition, adherence to the MedDiet fully mediated the association between intervention and reduction in GHG emissions by 56 % and energy use by 53 %.SIPublicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCL

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics