Search

Aims: There are controversial data on the ability of the components of mineral metabolism (vitamin D, phosphate, parathormone [PTH], fibroblast growth factor-23 [FGF23], and klotho) to predict cardiovascular events. In addition, it is unknown whether they add any prognostic value to other well-known biomarkers. Methods and results: In 969 stable coronary patients, we determined plasma levels of all the aforementioned components of mineral metabolism with a complete set of clinical and biochemical variables, including N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hs-TnI), and high-sensitivity C-reactive protein. Secondary outcomes were ischaemic events (any acute coronary syndrome, stroke, or transient ischaemic attack) and heart failure or death. The primary outcome was a composite of the secondary outcomes. Median follow-up was 5.39 years. Age was 60 (52–72) years. Median glomerular filtration rate was 80.4 (65.3–93.1) mL/min/1.73 m2. One-hundred and eighty-five patients developed the primary outcome. FGF23, PTH, hs-TnI, and NT-proBNP were directly related with the primary outcome on univariate Cox analysis, while Klotho and calcidiol were inversely related. On multivariate analysis, only PTH (HR 1.058 [CI 1.021–1.097]; P = 0.002) and NT-proBNP (HR 1.020 [CI 1.012–1.028]; P 85.5 RU/mL) (P, This work was supported by grants from Instituto de Salud Carlos III (ISCIII) and Fondos FEDER (Fondo Europeo de Desarrollo Regional) European Union (PI05/0451, PI14/1567, PI17/01615, and PI17/01495); Spanish Society of Cardiology; Spanish Society of Arteriosclerosis; RECAVA (Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares) (RD06/0014/0035); and Instituto de Salud Carlos III FEDER (FJD biobank: RD09/0076/00101). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Recent studies have raised the possibility of a role for lipoproteins, including high-density lipoprotein cholesterol (HDLc), in abdominal aortic aneurysm (AAA). The study was conducted in plasmas from 39 large size AAA patients (aortic diameter &gt, 50 mm), 81 small/medium size AAA patients (aortic diameter between 30 and 50 mm) and 38 control subjects (aortic diameter &lt, 30 mm). We evaluated the potential of HDL-mediated macrophage cholesterol efflux (MCE) to predict AAA growth and/or the need for surgery. MCE was impaired in the large aortic diameter AAA group as compared with that in the small/medium size AAA group and the control group. However, no significant difference in HDL-mediated MCE capacity was observed in 3 different progression subgroups (classified according to growth rate &lt, 1 mm per year, between 1 and 5 mm per year or &gt, 5 mm per year) in patients with small/medium size AAA. Moreover, no correlation was found between MCE capacity and the aneurysm growth rate. A multivariate Cox regression analysis revealed a significant association between lower MCE capacity with the need for surgery in all AAA patients. Nevertheless, the significance was lost when only small/medium size AAA patients were included. Our results suggest that MCE, a major HDL functional activity, is not involved in AAA progression.

16 p.-5 fig.-3 tab.-1 il. cent., BACKGROUND: The mechanisms underlying early atherosclerotic plaque formation are not completely understood. Moreover, plasma biomarkers of subclinical atherosclerosis are lacking., OBJECTIVES: The purpose of this study was to analyze the temporal and topologically resolved protein changes taking place in human aortas with early atherosclerosis to find new potential diagnostic and/or therapeutic targets., METHODS: The protein composition of healthy aortas (media layer) or with early atheroma (fatty streak and fibrolipidic, media and intima layers) was analyzed by deep quantitative multiplexed proteomics. Further analysis was performed by Western blot, immunohistochemistry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Plasma levels of complement C5 were analyzed in relation to the presence of generalized (>2 plaques) or incipient (0 to 2 plaques) subclinical atherosclerosis in 2 independent clinical cohorts (PESA [Progression of Early Subclinical Atherosclerosis] [n=360] and NEFRONA [National Observatory of Atherosclerosis in Nephrology] [n=394])., RESULTS: Proteins involved in lipid transport, complement system, immunoglobulin superfamily, and hemostasis are increased in early plaques. Components from the complement activation pathway were predominantly increased in the intima of fibrolipidic plaques. Among them, increased C5 protein levels were further confirmed by Western blot, enzyme-linked immunosorbent assay and immunohistochemistry, and associated with in situ complement activation. Plasma C5 was significantly increased in individuals with generalized subclinical atherosclerosis in both PESA and NEFRONA cohorts, independently of risk factors. Moreover, in the PESA study, C5 plasma levels positively correlated with global plaque volume and coronary calcification., CONCLUSIONS: Activation of the complement system is a major alteration in early atherosclerotic plaques and is reflected by increased C5 plasma levels, which have promising value as a novel circulating biomarker of subclinicalatherosclerosis., This study was funded by the Spanish MINECO(SAF2016-80843-R, BIO2015-67580-P, and PGC2018-097019-B-I00), CAM (Complemento II-CM, S2017/BMD-3673),Fondo de Investigaciones Sanitarias ISCiii-FEDER (Biobancos RD09/0076/00101) and PRB3 (IPT17/0019, ProteoRed), and FEDER “Una manera de hacer Europa.” CIBERCV is an Instituto de Salud Carlos III project. The work leading to these results has also received funding from “la Caixa” Banking Foundation under the project code HR17-00247. The PESA study is cofunded equally by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), and Banco Santander, Madrid, Spain. The study also receives funding from the Instituto de Salud Carlos III (PI15/02019) and the European Regional Development Fund (ERDF) “Una manera de hacer Europa.”

The aim of this evidence-based project was to improve the medical screening process, enhance medical decision-making, and standardize the utilization of an adult traumatic brain injury (TBI) neuroimaging guideline among advanced practice providers (APPs) in an urban emergency department (ED). Neuroimaging, specifically computed tomography (CT), helps identify life-threatening intracranial injuries when clinically appropriate. The literature supports the utilization of neuroimaging guidelines, clinical examinations, and provider expertise when identifying the need for a head CT scan. Although head CT scans are clinically useful, they increase health care costs and pose potential cancer risks from radiation exposure. Eight APPs (i.e., nurse practitioners, physician assistants) were trained in the American College of Emergency Physicians' (ACEP's) TBI clinical guideline with one-on-one education. Preintervention, retrospective, baseline data were collected for a period of 4 months (n = 152). Three months of postintervention data were collected to assess adherence to the guideline (n = 132), including physicians' charts that were reviewed as a comparison. The findings demonstrated a statistically significant reduction in head CT scans that did not meet ACEP criteria among APPs after training (p = 0.010). The results of this project suggest improved medical decision-making among APPs, avoidance of unnecessary costs, and a reduction in radiation exposure for patients. This project could be easily replicated in other ED settings using the ACEP TBI guideline as part of their standardized procedures, clinical policies, or protocols.

N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels are increased in patients with cancer. In this paper, we test whether NT-proBNP may identify patients who are going to receive a future cancer diagnosis (CD) in the intermediate-term follow-up. We studied 962 patients with stable coronary artery disease and free of cancer and heart failure at baseline. This sample represents a re-analysis of a previous work expanding the sample size and the follow-up. NT-proBNP, galectin-3, monocyte chemoattractant protein-1, high-sensitivity C-reactive protein, high-sensitivity cardiac troponin I (hsTnI), and calcidiol (vitamin D) plasma levels were assessed. The primary outcome was new CD. After 5.40 (2.81–6.94) years of follow-up, 59 patients received a CD. NT-proBNP [HR 1.036 CI (1.015–1.056) per increase in 100 pg/mL, p = 0.001], previous atrial fibrillation (HR 3.140 CI (1.196–8.243), p = 0.020), and absence of previous heart failure (HR 0.067 CI (0.006–0.802), p = 0.033) were independent predictors of receiving a CD in the first three years of follow-up. None of the variables analyzed predicted a CD beyond this time. The number of patients developing heart failure during follow-up was 0 (0.0%) in patients receiving CD in the first three years of follow-up, 2 (6.9%) in those receiving a CD diagnosis beyond this time, and 40 (4.4%) in patients not developing cancer (p = 0.216). These numbers suggest that future heart failure was not a confounding factor. In patients with coronary artery disease, NT-proBNP was an independent predictor of CD in the first three years of follow-up but not later, suggesting that it could be detecting subclinical undiagnosed cancers.

Abdominal aortic aneurysm (AAA) is characterised by the presence of B cells and immunoglobulins in the aortic wall, mainly in the adventitia. Kappa (κ) and lambda (λ) free light chains (FLCs) are produced from B cells during immunoglobulin synthesis. This study investigated the presence and prognostic value of combined FLCs (cFLCs or summed κ and λ) in patients with AAA. cFLCs were analysed by a turbidimetric specific assay in tissue conditioned media from AAA samples (n = 34) compared with healthy aortas (n = 34) from France and in plasma samples from patients with AAA (n = 434) and age matched controls (n = 104) selected from the Viborg Vascular (VIVA) AAA screening trial in Denmark. t test, logistic regression, and Cox regression were used to test whether plasma cFLCs serve as a marker for AAA presence and whether cFLCs were predictive of death, major adverse cardiovascular events (MACE), or major adverse lower limb events (MALE). Increased cFLC levels were detected in the AAA adventitial layer compared with the AAA medial layer and healthy media layer (13.65 ± 3.17 vs. 6.57 ± 1.01 vs. 0.49 ± 0.09 mg/L, respectively, p < .050). The upper tertile of plasma cFLCs was independently associated with AAA presence after correcting for confounders (odds ratio [OR] 7.596, 95% confidence intervals [CI] 3.117 - 18.513; p < .001). Of 434 patients with AAA, 89 (20.5%) died, 104 (24.0%) suffered MACE, and 63 (14.5%) suffered MALE, during a five year follow up. In univariable analysis, the cFLC upper tertile was associated with a higher risk of death, MACE, and MALE (p < .001 for all). After adjustment for confounders, cFLCs remained an independent predictor of all cause mortality (hazard ratio [HR] 4.310, 95% CI 2.157 - 8.609; p < .001), MACE (HR 2.153, 95% CI 1.218 - 3.804; p = .008), or MALE (HR 3.442, 95% CI 1.548 - 7.652; p = .002) for those in the upper tertile. Increased cFLCs are observed in adventitial tissue of patients with AAA, indicating local activation of B cells. Plasma cFLC levels are an independent predictor of death, MACE, and MALE in patients with AAA. This study was funded by the Spanish MINECO (PID2019- 106814RB-I00 and PGC2018-097019-B-I00), la Caixa Foundation (HR17-00247), CAM (S2017/BMD-3673), and Fondo de Investigaciones Sanitarias ISCiii-FEDER (PI19/ 00128). Sí

Altres ajuts: Comunidad Autónoma de Madrid (Complemento II-CM, S2017/BMD-3673); Fondo Europeo de Desarrollo Regional (FEDER); Fundació "La Caixa" (HR17-00247). High Density Lipoprotein (HDL) plays a protective role in abdominal aortic aneurysm (AAA); however, recent findings suggest that oxidative modifications could lead to dysfunctional HDL in AAA. This study aimed at testing the effect of oxidized HDL on aortic lesions and humoral immune responses in a mouse model of AAA induced by elastase, and evaluating whether antibodies against modified HDL can be found in AAA patients. HDL particles were oxidized with malondialdehyde (HDL-MDA) and the changes were studied by biochemical and proteomics approaches. Experimental AAA was induced in mice by elastase perfusion and then mice were treated with HDL-MDA, HDL or vehicle for 14 days. Aortic lesions were studied by histomorphometric analysis. Levels of anti-HDL-MDA IgG antibodies were measured by an in-house immunoassay in the mouse model, in human tissue-supernatants and in plasma samples from the VIVA cohort. HDL oxidation with MDA was confirmed by enhanced susceptibility to diene formation. Proteomics demonstrated the presence of MDA adducts on Lysine residues of HDL proteins, mainly ApoA-I. MDA-modification of HDL abrogated the protective effect of HDL on cultured endothelial cells as well as on AAA dilation in mice. Exposure to HDL-MDA elicited an anti-HDL-MDA IgG response in mice. Anti-HDL-MDA were also detected in tissue-conditioned media from AAA patients, mainly in intraluminal thrombus. Higher plasma levels of anti-HDL-MDA IgG antibodies were found in AAA patients compared to controls. Anti-HDL-MDA levels were associated with smoking and were independent predictors of overall mortality in AAA patients. Overall, MDA-oxidized HDL trigger a specific humoral immune response in mice. Besides, antibodies against HDL-MDA can be detected in tissue and plasma of AAA patients, suggesting its potential use as surrogate stable biomarkers of oxidative stress in AAA.

Clinical data indicate that patients with C-reactive protein (CRP) levels higher than 2 mg per liter suffer from persistent inflammation, which is associated with high risk of cardiovascular disease (CVD). We determined whether a panel of biomarkers associated with CVD could predict recurrent events in patients with low or persistent inflammation and coronary artery disease (CAD). We followed 917 patients with CAD (median 4.59 ± 2.39 years), assessing CRP, galectin-3, monocyte chemoattractant protein-1 (MCP-1), N-terminal fragment of brain natriuretic peptide (NT-proBNP) and troponin-I plasma levels. The primary outcome was the combination of cardiovascular events (acute coronary syndrome, stroke or transient ischemic event, heart failure or death). Patients with persistent inflammation (n = 343) showed higher NT-proBNP and MCP-1 plasma levels compared to patients with CRP &lt, 2 mg/L. Neither MCP-1 nor NT-proBNP was associated with primary outcome in patients with CRP &lt, 2 mg/L. However, NT-proBNP and MCP-1 plasma levels were associated with increased risk of the primary outcome in patients with persistent inflammation. When patients were divided by type of event, MCP-1 was associated with an increased risk of acute ischemic events. A significant interaction between MCP-1 and persistent inflammation was found (synergy index: 6.17 (4.39–7.95)). In conclusion, MCP-1 plasma concentration is associated with recurrent cardiovascular events in patients with persistent inflammation.

Background: High-density lipoproteins (HDL) are a complex mixture of lipids and proteins with vasculoprotective properties. However, HDL components could suffer post-translational modifications (PTMs) under pathological conditions, leading to dysfunctional HDL. We studied whether HDL are modified in abdominal aortic aneurysm (AAA) and the effect on HDL functionality. Methods: HDL were isolated by ultracentrifugation from AAA tissue (HDL-T) and from plasma of healthy volunteers and then incubated with AAA tissue-conditioned medium (HDL-AAA CM). PTMs from these particles were characterized using Comet-PTM. The ability of HDL-AAA CM for promoting cholesterol efflux was determined ex vivo and in vivo by using J774A.1 [ 3 H]cholesterol-labeled mouse macrophages and after injecting [ 3 H]cholesterol-labeled mouse macrophages and HDL into the peritoneal cavity of wild-type C57BL/6 mice, respectively. Trp50 and Trp108 oxidized forms of APOA1 in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients and controls were measured by targeted parallel reaction monitoring. Findings: Oxidation was the most prevalent PTM in apolipoproteins, particularly in APOA1. Trp50 and Trp108 in APOA1 were the residues most clearly affected by oxidation in HDL-T and in HDL-AAA CM, when compared to their controls. In addition, cholesterol efflux was decreased in macrophages incubated with HDL-AAA CM in vitro and a decreased macrophage-to-serum reverse cholesterol transport was also observed in mice injected with HDL-AAA CM. Finally, both oxidized Trp50 and Trp108 forms of APOA1 were increased in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients in relation to controls. Interpretation: Oxidative modifications of HDL present in AAA tissue and plasma were closely associated with the loss of vasculoprotective properties of HDL in AAA. Fund: MINECO, ISCiii-FEDER, CIBERDEM, CIBERCV and LA CAIXA., This work was partly funded by the Spanish MINECO (SAF2016- 80843-R and BIO2015-67580-P), Fondo de Investigaciones Sanitarias ISCiii-FEDER (Biobancos RD09/0076/00101, and ProteoRed PRB2 IPT13/0001 and PRB3 PT17/0019), Instituto de Salud Carlos III (PI1600139), and FEDER “Una manera de hacer Europa”, CIBERDEM and CIBERCV are Instituto de Salud Carlos III projects. The project leading to these results has also received funding from “la Caixa” Banking Foundation under the project code HR17-00247. The CNIC is supported by the MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505)

Introduction Type-2 diabetes mellitus (T2DM) is associated with early and severe atherosclerosis. However, few biomarkers can predict cardiovascular events in this population. Methods We followed 964 patients with coronary artery disease (CAD), assessing at baseline galectin-3, monocyte chemoattractant protein-1 (MCP-1) and N-terminal fragment of brain natriuretic peptide (NT-proBNP) plasma levels. Secondary outcomes were acute ischemia and heart failure or death. Primary outcome was the combination of the secondary outcomes. Results Male patients were 75.0% in T2DM and 76.6% in the non-T2DM subgroup (p=0.609). Age was 61.0 (54–72) and 60.0 (51–71) years, respectively (p=0.092). 232 patients had T2DM. Patients with T2DM showed higher MCP-1 [144 (113–195) vs. 133 (105–173) pg/ml, p=0.006] and galectin-3 [8.3 (6.5–10.5) vs. 7.8 (5.9–9.8) ng/ml, p=0.049] levels. Median follow-up was 5.39 years (2.81- 6.92). Galectin-3 levels were associated with increased risk of the primary outcome in T2DM patients [HR 1.57 (1.07–2.30); p=0.022], along with a history of cerebrovascular events. Treatment with clopidogrel was associated with lower risk. In contrast, NT-proBNP and MCP-1, but not galectin-3, were related to increased risk of the event in non-diabetic patients [HR 1.21 (1.04–1.42); p=0.017 and HR 1.23 (1.05–1.44); p=0.012, respectively], along with male sex and age. Galectin-3 was also the only biomarker that predicted the development of acute ischemic events and heart failure or death in T2DM patients, while in non-diabetics MCP-1 and NT-proBNP, respectively, predicted these events. Conclusion In CAD patients, cardiovascular events are predicted by galectin-3 plasma levels in patients with T2DM, and by MCP-1 and NT-proBNP in those without T2DM. Effect of Gal-3 on the primary endpoint Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Insituto de Salud Carlos III

Our purpose was to assess a possible association of inflammatory, lipid and mineral metabolism biomarkers with coronary artery ectasia (CAE) and to determine a possible association of this with acute atherotrombotic events (AAT). We studied 270 patients who underwent coronary angiography during an acute coronary syndrome 6 months before. Plasma levels of several biomarkers were assessed, and patients were followed during a median of 5.35 (3.88&ndash, 6.65) years. Two interventional cardiologists reviewed the coronary angiograms, diagnosing CAE according to previously published criteria in 23 patients (8.5%). Multivariate binary logistic regression analysis was used to search for independent predictors of CAE. Multivariate analysis revealed that, aside from gender and a diagnosis of dyslipidemia, only monocyte chemoattractant protein-1 (MCP-1) (OR = 2.25, 95%CI = (1.35&ndash, 3.76) for each increase of 100 pg/mL, p = 0.001) was independent predictor of CAE, whereas mineral metabolism markers or proprotein convertase subtilisin/kexin type 9 were not. Moreover, CAE was a strong predictor of AAT during follow-up after adjustment for other clinically relevant variables (HR = 2.67, 95%CI = (1.22&ndash, 5.82), p = 0.013). This is the first report showing that MCP-1 is an independent predictor of CAE, suggesting that CAE and coronary artery disease may share pathogenic mechanisms. Furthermore, CAE was associated with an increased incidence of AAT.

espanolLa pandemia por la nueva infeccion respiratoria conocida como enfermedad coronavirus 2019 (COVID-19), causada por el virus SARS-CoV-2, ha desencadenado una perturbacion sin precedentes en la actividad habitual de los servicios de cirugia oral y maxilofacial en Espana, retrasando la atencion rutinaria de pacientes e intervenciones quirurgicas programadas. Los cirujanos orales y maxilofaciales son uno de los colectivos sanitarios con mayor riesgo de infeccion nosocomial por el estrecho contacto que se produce con los pacientes asintomaticos y sintomaticos con infeccion por SARS-CoV-2 a traves de la cavidad oral y orofaringe. El proposito del presente documento ha sido actualizar la evidencia disponible para el manejo y tratamiento seguro y efectivo en consulta, cirugias ambulatorias, programadas y urgentes y hospitalizacion, minimizando al mismo tiempo, tanto como sea posible, el riesgo de contagio para el cirujano oral y maxilofacial, personal sanitario y pacientes. Este documento pretende esclarecer los aspectos mas significativos y crear un protocolo comun de manejo de pacientes con COVID-19 en cirugia oral y maxilofacial durante la fase aguda de propagacion y de control posterior de la pandemia en nuestro pais. EnglishThe pandemic due to the new respiratory infection known as coronavirus 2019 disease (COVID-19), caused by the SARS-CoV-2 virus, has triggered an unprecedented disruption in the normal activity of oral and maxillofacial surgery departments in Spain, delaying routine patient care and elective surgical interventions. Oral and maxillofacial surgeons are one of the healthcare groups with the highest risk of nosocomial infection because of the close contact that occurs with asymptomatic and symptomatic patients with SARS-CoV-2 infection through the oral cavity and oropharynx. The purpose of this document has been to update the available evidence for the safe and effective management and treatment in outpatient clinic, ambulatory, elective and emergency surgeries, and hospitalization, while minimizing as much as possible the risk of infection for the oral and maxillofacial surgeon, health workers and patients. This document aims to clarify the most significant aspects and create a common protocol for the management of patients with COVID-19 in oral and maxillofacial surgery during the acute stage of spread and subsequent control of the pandemic in our country.

espanolAntecedentes y objetivo: La edad de los pacientes ingresados para tratamiento por los servicios de cirugia oral y maxilofacial (COMF) es progresivamente mas alta, con la comorbilidad asociada que eso conlleva, y supone un incremento sustancial de las interconsultas a los servicios de medicina interna (MI), que no alcanzan la efectividad requerida. Una alternativa para mejorar la atencion a los pacientes es la colaboracion entre ambos servicios mediante la asistencia compartida (AC). El objetivo de este articulo es estudiar la repercusion y el efecto del empleo de la AC en los pacientes de COMF. Metodos: Estudio observacional retrospectivo de los pacientes ≥ 16 anos ingresados desde el 12 de marzo de 2017 hasta el 12 de marzo de 2019 en COMF, con AC con MI desde el 12 de marzo de 2018. Las variables analizadas son edad, sexo, tipo de ingreso, si fue intervenido quirurgicamente, peso administrativo asociado a GRD, numero total de diagnosticos al alta, indice de comorbilidad de Charlson (ICh), exitus, reingresos urgentes y estancia hospitalaria. Resultados: Los pacientes con AC fueron de menor edad (2,8 anos, intervalo de confianza del 95 % [IC 95 %] 0,1 a 5,6), pero con mayor numero de diagnosticos (0,8; IC 95 % 0,4 a 1,2) y una tendencia a mayor ICh (0,3; IC 95 % -0,1 a 0,6) y peso administrativo (0,04; IC 95 % -0,03 a 0,1). Al ajustar, observamos que la AC redujo el 22,7 % la estancia en CMF, 1 dia (IC 95 % -1,8 a -0,3), el 40 % los reingresos urgentes y el 50 % la mortalidad, ambos no significativos. El descenso de la estancia supone una disminucion de costes de, como minimo, 231.816,7 €. Conclusiones: La edad de los enfermos ingresados para tratamiento por los servicios de cirugia oral y maxilofacial es cada vez mas alta, que se asocia con una mayor comorbilidad. El empleo de la asistencia compartida con medicina interna en el manejo de los pacientes ingresados en cirugia oral y maxilofacial se asocia a una disminucion de la estancia y los costes, en linea con lo observado en otros servicios quirurgicos. EnglishBackground and objective: The age of patients admitted for treatment by Oral and Maxillofacial Surgery (OMFS) services is progressively higher, with the associated comorbidity that this entails, and supposes a substantial increase in referrals to the Internal Medicine (IM) services, which do not reach the required effectiveness. An alternative to improve patient care is collaboration between both services through shared care (SC). The objective of this article is to study the repercussion and effect of the use of shared care in Oral and Maxillofacial patients. Methods: Retrospective observational study of patients aged ≥ 16 years admitted from 3/12/2017 to 3/12/2019 at OMFS, with SC with IM from 3/12/2018. The variables analyzed are age, sex, type of admission, whether the patient underwent surgery, administrative weight associated with DRG, total number of diagnoses at discharge, Charlson's comorbidity index (HCI), death, urgent readmissions and hospital stay. Results: Patients with AC were younger (2.8 years, 95 % confidence interval [95 % CI] 0.1 to 5.6), but with a greater number of diagnoses (0.8, 95 % CI 0.4 to 1.2) and a trend towards higher CIh (0.3; 95 % CI -0.1 to 0.6) and administrative weight (0.04; 95 % CI -0.03 to 0.1 ). When adjusting, we observed that CA reduced the stay in the CMF by 22.7 %, 1 day (CI 95 % -1.8 to -0.3), 40 % the urgent readmissions and 50 % the mortality, both not significant. The decrease in the stay implies a reduction in costs of, at least, € 231,816.7. Conclusions: The age of patients admitted for treatment by Oral and Maxillofacial Surgery services is increasingly higher, which is associated with greater comorbidity. The use of shared care with Internal Medicine in the management of patients admitted to Oral and Maxillofacial Surgery is associated with a decrease in stay and costs, in line with what was observed in other surgical services.

High-density lipoproteins cholesterol (HDLc) levels are decreased in abdominal aortic aneurysm (AAA), which is hallmarked by autoimmunity and lipid aortic deposits. To investigate whether IgG anti-HDL antibodies were present in AAA and their potential association with clinical features, IgG anti-HDL and total IgG along with HDLc plasma levels were measured in 488 AAA patients and 184 controls from the Viborg Vascular (VIVA) study, and in tissue-conditioned media from AAA intraluminal thrombus and media layer samples compared to control aortas. Higher IgG anti-HDL levels were found in AAA compared to controls, even after correcting for total IgG, and after adjusting for potential confounders. IgG anti-HDL levels were correlated with aortic diameter in univariate and adjusted multivariate analyses. IgG anti-HDL antibodies were negatively associated with HDLc levels before and after correcting for potential confounders. Increased anti-HDL antibodies were identified in tissue-conditioned media from AAA samples compared to healthy aortas, with higher levels being observed in the media layer. In conclusion, increased IgG anti-HDL levels (both in plasma and in tissue) are linked to AAA, associated with aortic diameter and HDLc levels. These data suggest a potential immune response against HDL in AAA and support an emerging role of anti-HDL antibodies in AAA.

Introduction Abdominal aortic aneurysm (AAA) is a multifactorial vascular disease characterized by chronic inflammation, oxidative stress and proteolytic activity in the aortic wall, which contribute to extracellular matrix degradation and aortic dilation. Altered expression and activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have been implicated in several cardiovascular diseases including atherosclerosis and aneurysm formation. Suppressors of cytokine signaling (SOCS) are key negative regulators of JAK/STAT pathway and have been considered an attractive target for therapeutic intervention. AIM We hypothesize that SOCS1 protein could influence AAA development by inhibiting JAK activity and, consequently, STAT activation and target gene expression. Therefore, this study investigates the effect of a SOCS1-derived synthetic peptide in a rodent model of AAA and in cultured vascular smooth muscle cells (VSMC). Methods Experimental AAA was induced in C57BL/6 mice (males, 12 weeks old) by transient elastase perfusion of the aorta. Mice were randomly divided into control (vehicle, i.p.) and treatment (SOCS1 peptide, 3 mg/kg/day, i.p.) groups. Fourteen days after AAA induction, mice were sacrificed, and aorta segments were collected for histology (n=10/group) and mRNA and protein expression analysis (n=8/group). Results Compared to the AAA control group, SOCS1-treated mice exhibited a significant decrease in aortic diameter (68±6% vs. control; p Conclusion Our results suggest that SOCS1 peptide presents protective effects in experimental AAA by suppressing JAK/STAT pathway-mediated inflammation. Acknowledgement/Funding MINECO-FEDER (SAF2015-63696-R), ISCII (FIS-FEDER PI17/01495), Spanish Society of Arteriosclerosis.

Background and aim Abdominal aortic aneurysm (AAA) is a degenerative disorder characterized by a localized and permanent dilation of the aorta. Pathological features of AAA include proteolysis, vascular smooth muscle cells (VSMC) apoptosis, oxidative stress and inflammation. Previous studies have demonstrated the role of innate and adaptive immunity in the initiation and progression of AAA. However, the specific mechanisms of humoral, antibody-mediated, immune response elicited by self and non-self-antigens are not completely known. IgG Fc receptors (FcgammaR) play an important role in the initiation and regulation of many immunological and inflammatory processes, thus providing a link between humoral and cellular immune responses. In this work, we focus on IgG immune response against antigens exposed in the damaged vessel, analysing the specific role played by FcgammaR in the pathogenesis of AAA. Methods and results AAA was induced by aortic elastase perfusion in wild-type (WT) C57BL/6 mice (n=24 males, 12 weeks old). Compared with healthy aortas, AAA tissue showed IgG and IgM deposition and increased expression levels of activating (IA, IIIA and IVA) and inhibitory (IIB) FcgammaR (5-, 3-, 10, and 2-fold increases; p Conclusion Activating FcgammaR participate in AAA formation by promoting inflammatory cell recruitment, and cytokine and matrix-degrading protease expression. Therefore, modulation of FcgammaR-dependent responses could be a promising therapeutic option for the treatment of AAA. Acknowledgement/Funding MINECO/FEDER (SAF2015-63696-R), ISCIII (FIS/FEDER PI17/01495), Spanish Society of Arteriosclerosis, La Caixa (HR17-00247), Conchita Rabago Foundation

Chronic elbow pain can be caused by lateral and medial epicondylosis, common extensor and flexor tendinopathy, and osteoarthritis of the radio-humeral and humero-ulnar joints. Ultrasound-guided injections and tenotomies can be an effective option when conservative treatments, including activity modifications and physical therapy, have been tried and failed. When injecting tendons the placement of the needle should be checked in two planes to ensure injectate spreads where intended. When injecting the common flexor tendon and the medial epicondyle, the position of the ulnar nerve should be checked to ensure that it is not subluxed. When injecting the common extensor tendon, one must be aware that the radial collateral ligament is located just underneath. If using steroids, one should use the lowest possible doses and volumes to minimize the possibility of weakening of the tendons, ligaments, and cartilage.

Cardiovascular diseases (CVD) remain the major cause of morbidity and mortality in Europe. The clinical complications associated to arterial wall rupture involve intimal cap rupture in complicated atherosclerotic plaques and medial rupture in abdominal aortic aneurysm (AAA). The mechanisms underlying pathological vascular remodeling include lipid accumulation, cell proliferation, redox imbalance, proteolysis, leukocyte infiltration, cell death, and eventually, thrombosis. The complement system could participate in vascular remodeling by several mechanisms, from an initial protective response that aims in the clearing of cell debris to a potential deleterious role participating in leukocyte chemotaxis and cell activation and bridging innate and adaptive immunity. We have reviewed the presence and distribution of complement components, as well as the triggers of complement activation in atherosclerotic plaques and AAA, to later assess the functional consequences of complement modulation in experimental models of pathological vascular remodeling and the potential role of complement components as potential circulating biomarkers of CVD. On the whole, complement system is a key mechanism involved in vascular remodelling, which could be useful in the diagnostic/prognostic setting, as well as a potential therapeutic target, of CVD.

[ES] El aneurisma de aorta abdominal (AAA) es una patología vascular con una elevada tasa de morbimortalidad y una prevalencia que, en varones de más de 65 años, puede alcanzar el 8%. En esta enfermedad, habitualmente asintomática, se produce una dilatación progresiva de la pared vascular que puede llevar a su rotura, un fenómeno mortal en más de un 80% de los casos. El tratamiento de los pacientes con aneurismas asintomáticos se limita al seguimiento periódico con pruebas de imagen, el control de los factores de riesgo cardiovascular y un tratamiento con terapia antiagregante y estatinas, si bien actualmente no existe ningún tratamiento farmacológico efectivo capaz de limitar su progresión o evitar su rotura. En la actualidad el diámetro aórtico es el único marcador de riesgo de rotura y determina la necesidad de reparación quirúrgica cuando alcanza valores superiores a 5,5 cm. En esta revisión se tratan los principales aspectos relacionados con la epidemiología, los factores de riesgo, el diagnóstico y el manejo terapéutico del AAA, se exponen las dificultades para disponer de buenos biomarcadores de esta enfermedad y se describen las estrategias para la identificación de nuevas dianas terapéuticas y biomarcadores en el AAA., [EN] Abdominal aortic aneurysm (AAA) is a vascular pathology with a high rate of morbidity and mortality and a prevalence that, in men over 65 years, can reach around 8%. In this disease, usually asymptomatic, there is a progressive dilatation of the vascular wall that can lead to its rupture, a fatal phenomenon in more than 80% of cases. The treatment of patients with asymptomatic aneurysms is limited to periodic monitoring with imaging tests, control of cardiovascular risk factors and treatment with statins and antiplatelet therapy. There is no effective pharmacological treatment capable of limiting AAA progression or avoiding their rupture. At present, the aortic diameter is the only marker of risk of rupture and determines the need for surgical repair when it reaches values greater than 5.5 cm. This review addresses the main aspects related to epidemiology, risk factors, diagnosis and clinical management of AAA, exposes the difficulties to have good biomarkers of this pathology and describes the strategies for the identification of new therapeutic targets and biomarkers in AAA., The laboratory work carried out by JLMV and CR was funded by the Instituto de Salud Carlos III [Carlos III Health Institute] (PI15/01016 and PI16/01419) and the Ministry of Economy, Industry and Competition (SAF SAF2015- 64767-R and SAF2016-80843-R), with co-funding by the European Regional Development Fund (ERDF). The Biomedical Research Network Centres (CIBER) for Cardiovascular Diseases is an ISCIII initiative. LC received a grant from the funds for the training and contracting of new research staff (FI) programme of the Agència de Gestió d’Ajuts Universitaris i de Recerca [Agency for the Management of University and Research Grants] (2017FI B 00175, Regional Government of Catalonia).

Chronic and acute shoulder pain and dysfunction are common complaints among patients. Shoulder pain may be the result of abnormality involving the rotator cuff, subacromial-subdeltoid bursa, biceps tendon, glenoid labrum, glenohumeral joint, acromioclavicular joint, sternoclavicular joint, or glenohumeral joint capsule. Ultrasound-guided (USG) procedures of the shoulder are well established for interventional management. Ultrasound provides the advantages of excellent soft tissue resolution, injection accuracy, low cost, accessibility, portability, lack of ionizing radiation, and the ability to perform real-time image-guided procedures. The purpose of this article is to review common indications and effective techniques for USG injections about the shoulder.

Abdominal aortic aneurysm (AAA) is a permanent dilation of the aorta due to excessive proteolytic, oxidative and inflammatory injury of the aortic wall. We aimed to identify novel mediators involved in AAA pathophysiology, which could lead to novel therapeutic approaches. For that purpose, plasma from four AAA patients and four controls were analysed by a label-free proteomic approach. Among identified proteins, paraoxonase-1 (PON1) was decreased in plasma of AAA patients compared with controls, which was further validated in a bigger cohort of samples by ELISA. The phenylesterase enzymatic activity of PON1 was also decreased in serum of AAA patients compared with controls. To address the potential role of PON1 as a mediator of AAA, experimental AAA was induced by aortic elastase perfusion in wild-type (WT) mice and human transgenic PON1 (HuTgPON1) mice. Similar to humans, PON1 activity was also decreased in serum of elastase-induced AAA mice compared with healthy mice. Interestingly, overexpression of PON1 was accompanied by smaller aortic dilation and higher elastin and vascular smooth muscle cell (VSMC) content in the AAA of HuTgPON1 compared with WT mice. Moreover, HuTgPON1 mice display decreased oxidative stress and apoptosis, as well as macrophage infiltration and monocyte chemoattractant protein-1 (MCP1) expression, in elastase-induced AAA. In conclusion, decreased circulating PON1 activity is associated with human and experimental AAA. PON1 overexpression in mice protects against AAA progression by reducing oxidative stress, apoptosis and inflammation, suggesting that strategies aimed at increasing PON1 activity could prevent AAA.

BACKGROUND AND OBJECTIVES: Soluble TNF-like weak inducer of apoptosis (sTWEAK) is a proinflammatory cytokine belonging to the TNF superfamily. sTWEAK concentrations have been associated with the presence of CKD and cardiovascular disease (CVD). We hypothesized that sTWEAK levels may relate to a higher prevalence of atherosclerotic plaques, vascular calcification, and cardiovascular outcomes observed in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 4-year prospective, multicenter, longitudinal study was conducted in 1058 patients with CKD stages 3-5D (mean age =58±13 years old; 665 men) but without any history of CVD from the NEFRONA Study (a study design on the prevalence of surrogate markers of CVD). Ankle-brachial index and B-mode ultrasound were performed to detect the presence of carotid and/or femoral atherosclerotic plaques together with biochemical measurements and sTWEAK assessment. Patients were followed for cardiovascular outcomes (follow-up of 3.13±1.15 years). RESULTS: Patients with more advanced CKD had lower sTWEAK levels. sTWEAK concentrations were independently and negatively associated with carotid intima-media thickness. sTWEAK levels were lower in patients with carotid atherosclerotic plaques but not in those with femoral plaques. After adjustment by confounders, the odds ratio (OR) for presenting carotid atherosclerotic plaques in patients in the lowest versus highest tertile of sTWEAK was 4.18 (95% confidence interval [95% CI], 2.89 to 6.08; P

BACKGROUND: Increased hemoglobin (Hb) accumulation was reported in abdominal aortic aneurysms (AAAs). CD163 is a macrophage receptor involved in tissue Hb clearance, however its role in AAA has not been reported. We investigated the role of Hb on monocyte recruitment and differentiation towards CD163 expressing macrophages ex vivo, in vitro and in human AAA.METHODS AND RESULTS: CD163 mRNA and protein expression was significantly higher in human AAA (n=7) vs. healthy wall (n=6). CD163 was predominantly found in adventitia of AAA, coinciding with areas rich in hemosiderin and adjacent to neoangiogenic microvessels. Dual CD14/CD163 expression was observed in recently infiltrated monocytes surrounding microvessels. A higher release of soluble CD163 was observed in the conditioned medium from AAA (AAA-CM, n=10), mainly in the adventitial layer. Similar to Hb, AAA-CM induced CD163-dependent monocyte chemotaxis, especially on circulating monocytes from AAA patients. Hb or AAA-CM promoted differentiation towards CD163(high)/HLA-DR(low)-expressing macrophages, with enhanced Hb uptake, increased anti-inflammatory IL-10 secretion and decreased pro-inflammatory IL-12p40 release. All these effects were partially suppressed when Hb was removed from AAA-CM. Separate analysis on circulating monocytes reported increased percentage of pre-infiltrating CD14(++)CD16(+) monocytes in patients with AAA (n=21), as compared to controls (n=14). A significant increase in CD163 expression in CD14(++)CD16(+) monocyte subpopulation was observed in AAA patients.CONCLUSIONS: The presence of Hb in the adventitial AAA-wall promotes the migration and differentiation of activated circulating monocytes in AAA patients, explaining the existence of a protective CD163-macrophage phenotype that could take up the Hb present in the AAA-wall, avoiding its injurious effects.

Introduction: Type-2 diabetes mellitus (T2DM) is associated with early and severe atherosclerosis. However, few biomarkers can predict cardiovascular events in this population. Methods: We followed 964 patients with coronary artery disease (CAD), assessing plasma levels of galectin-3, monocyte chemoattractant protein-1 (MCP-1), and N-terminal fragment of brain natriuretic peptide (NT-proBNP) at baseline. The secondary outcomes were acute ischemia and heart failure or death. The primary outcome was the combination of the secondary outcomes. Results. Two hundred thirty-two patients had T2DM. Patients with T2DM showed higher MCP-1 (144 (113&ndash, 195) vs. 133 (105&ndash, 173) pg/mL, p = 0.006) and galectin-3 (8.3 (6.5&ndash, 10.5) vs. 7.8 (5.9&ndash, 9.8) ng/mL, p = 0.049) levels as compared to patients without diabetes. Median follow-up was 5.39 years (2.81&ndash, 6.92). Galectin-3 levels were associated with increased risk of the primary outcome in T2DM patients (Hazard ratio (HR) 1.57 (1.07&ndash, 2.30), p = 0.022), along with a history of cerebrovascular events. Treatment with clopidogrel was associated with lower risk. In contrast, NT-proBNP and MCP-1, but not galectin-3, were related to increased risk of the event in nondiabetic patients (HR 1.21 (1.04&ndash, 1.42), p = 0.017 and HR 1.23 (1.05&ndash, 1.44), p = 0.012, respectively), along with male sex and age. Galectin-3 was also the only biomarker associated with the development of acute ischemic events and heart failure or death in T2DM patients, while, in nondiabetics, MCP-1 and NT-proBNP, respectively, were related to these events. Conclusion: In CAD patients, galectin-3 plasma levels are associated with cardiovascular events in patients with T2DM, and MCP-1 and NT-proBNP in those without T2DM.

BACKGROUND AND AIMS: Vascular calcification (VC) and atherosclerosis are associated with an increased cardiovascular morbimortality in chronic kidney disease (CKD). Osteoprotegerin (OPG) and osteopontin (OPN) are involved in both VC and CKD. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has been related to cardiovascular disease. We hypothesized that OPG, OPN and sTWEAK levels may be associated with a higher prevalence of cardiovascular outcomes in patients with CKD. METHODS: The presence of calcified or non-calcified atherosclerotic plaques was assessed in 1043 stage 3 to 5D CKD patients from The NEFRONA Study. Biochemical measurements and OPG, OPN and sTWEAK serum levels were analyzed. Patients were followed for cardiovascular outcomes (41 ± 16 months). RESULTS: At recruitment, 26% of CKD patients had VC. The adjusted odds ratios for having VC were 2.22 (1.32-3.75); p=.003 for OPG, and 0.45 (0.24-0.84); p=.01 for sTWEAK concentrations. After follow-up, 95 CV events occurred. In a Cox model, patients with OPG or OPN above and sTWEAK below their optimal cut-off points had an adjusted higher risk of cardiovascular events [HR: 2.10 (1.49-3.90); p=.02; 1.65 (1.02-2.65); p=.04; 2.05 (1.28-3.29), p=.003; respectively]. When CKD patients were grouped according to the number of biomarkers above (OPG and OPN) or below (sTWEAK) their cut-off points, the combination of these biomarkers showed the highest risk for cardiovascular events [HR: 9.46 (3.80-23.5) p

Reduced soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) levels have been related with cardiovascular disease. However, there are no data on the relationship between sTWEAK and atherosclerotic burden in subjects with or without cardiovascular risk factors but free from clinical disease. We have analyzed the association between circulating sTWEAK levels and the presence of carotid and/or femoral atherosclerotic plaques in subjects without known vascular disease.A multicenter, cross-sectional study was conducted in 448 subjects free from clinical CVD. B-mode ultrasound was performed to detect the presence of carotid and/or femoral atherosclerotic plaques. sTWEAK concentrations were measured by enzyme-linked immunosorbent assay.sTWEAK serum levels were reduced in parallel with an increment in cardiovascular risk factors. sTWEAK concentrations were independently and negatively associated with carotid intima/media thickness. Subjects with atherosclerotic plaques showed a reduction in sTWEAK levels [808 (645-963) vs 993 (830-1278); p 0.001]. A gradual decrease in sTWEAK levels was observed as the number of atherosclerotic plaques increased in our studied population. When we analyzed sTWEAK levels according to the vascular territory affected, we observed that sTWEAK concentrations were only diminished in subjects with carotid atherosclerotic plaques but not in those with femoral plaques. Following adjustment for various confounders, the OR for presenting carotid atherosclerotic plaque in subjects in lower vs higher tertile of sTWEAK levels was 8.09 [4.30-15.23; median (IQR); p 0.001].Diminished sTWEAK concentrations were significantly and independently associated with the presence of carotid atherosclerotic plaques in asymptomatic subjects.

This is the peer reviewed version of the following article: Clinica e Investigacion en Arterioesclerosis 27.2 (2015) which has been published in final form at http://dx.doi.org/10.1016/j.arteri.2014.06.003

AIM Interaction of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) with its receptor Fn14 accelerates atherosclerotic plaque development in ApoE deficient mice (ApoE KO). In this work, an analysis has been made on the effect of an HMG-CoA reductase inhibitor, atorvastatin, on atherosclerotic plaque development accelerated by TWEAK in ApoE KO mice. MATERIALS AND METHODS Eight week-old ApoE KO mice were fed with a high cholesterol diet for 4 weeks. The animals were then randomized into 3 groups: mice injected i.p. with saline, recombinant TWEAK (10 μg/kg/twice a week), or recombinant TWEAK plus atorvastatin (1 mg/kg/day) for 4 weeks. The lesion size, cellular composition, lipid and collagen content were analyzed, as well as inflammatory response in atherosclerotic plaques present in aortic root of mice. RESULTS TWEAK treated mice showed an increase in atherosclerotic plaque size, as well as in collagen/lipid ratio compared with control mice. In addition, macrophage content, MCP-1 and RANTES expression, and NF-κB activation were augmented in atherosclerotic plaques present in aortic root of TWEAK treated mice compared with control mice. Treatment with atorvastatin prevented all these changes induced by TWEAK in atherosclerotic lesions. Atorvastatin treatment also decreased Fn14 expression in the atherosclerotic plaques of ApoE KO mice. CONCLUSIONS Atorvastatin prevents the pro-atherogenic effects induced by TWEAK in ApoE KO mice, which could be related to the inhibition of Fn14 expression. The results of this study provide new information on the beneficial effects of statin treatment in cardiovascular diseases.

Interest in regenerative medicine for treating musculoskeletal pathology has grown tremendously over the past decade. Part of its appeal lies in the ability to use a patient׳s own cells to potentially heal acute and chronic injuries. While evidence grows supporting its use in certain injuries, a perception exists that regenerative medicine may be a panacea. In this article, we review the evidence for platelet-rich plasma and bone marrow aspirate concentrate in treating muscle, ligament, and fibrocartilage injuries. We also offer our own practice experiences and technical considerations in the uses of these techniques.

Background Chronic diseases have become a main cause of morbidity and mortality provoking function loss in organs. Quality of life is poor and expensive with replacement therapy. Transplantation offers a higher survival rate and a better life; however, the donation rate in Mexico is low, making it important to know the opinion of the population. Methods Six hundred forty-two people in Guanajuato, Mexico, (>15 years old) were enrolled. Demographic characteristics, education, religion, organ donation, and transplantation attitudes were evaluated. Results Donation attitudes in life or death were: very willing to donation (82.8% vs 61.5%), refuse to donate (12.7% vs 29.4%), and undecided (4.5% vs 9.1%). Reasons for donation were: altruism (63%), being useful to someone (28.6%), and empathy (7.1%). Negative causes were: personal beliefs (35.6%), fear (23.7%), and ignorance or “I don't know the recipient” (18.5%). Finally, 94.5% of the population is willing to receive a transplant if they need it. Conclusions Guanajuato has a high tendency to donate their own organs, but less to donate from a family member. Refusal to donate has originated from lack/misinformation that people received from health professionals. Although most people are willing to donate, this is not reflected in donation rates. To be able to make this intention reality, we must create educational models for health care personnel that will allow them to transmit proper information to the population.

Abdominal aortic aneurysm (AAA) evolution is unpredictable and no specific treatment exists for AAA, except surgery to prevent aortic rupture. Galectin-3 has been previously associated with CVD, but its potential role in AAA has not been addressed. Galectin-3 levels were increased in the plasma of AAA patients (n=225) compared with the control group (n=100). In addition, galectin-3 concentrations were associated with the need for surgical repair, independently of potential confounding factors. Galectin-3 mRNA and protein expression were increased in human AAA samples compared with healthy aortas. Experimental AAA in mice was induced via aortic elastase perfusion. Mice were treated intravenously with the galectin-3 inhibitor modified citrus pectin (MCP, 10 mg/kg, every other day) or saline. Similar to humans, galectin-3 serum and aortic mRNA levels were also increased in elastase-induced AAA mice compared with control mice. Mice treated with MCP showed decreased aortic dilation, as well as elastin degradation, vascular smooth muscle cell (VSMC) loss, and macrophage content at day 14 postelastase perfusion compared with control mice. The underlying mechanism(s) of the protective effect of MCP was associated with a decrease in galectin-3 and cytokine (mainly CCL5) mRNA and protein expression. Interestingly, galectin-3 induced CCL5 expression by a mechanism involving STAT3 activation in VSMC. Accordingly, MCP treatment decreased STAT3 phosphorylation in elastase-induced AAA. In conclusion, increased galectin-3 levels are associated with AAA progression, while galectin-3 inhibition decreased experimental AAA development. Our data suggest the potential role of galectin-3 as a therapeutic target in AAA.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK/Tnfsf12) is a cytokine implicated in different steps associated with vascular remodeling. However, the role of TWEAK under hyperglycemic conditions is currently unknown. Using two different approaches, genetic deletion of Tnfsf12 and treatment with a TWEAK blocking mAb, we have analyzed the effect of TWEAK inhibition on atherosclerotic plaque progression and stability in streptozotocin-induced diabetic ApoE deficient mice. Genetic inactivation of Tnfsf12 reduced atherosclerosis extension and severity in diabetic ApoE deficient mice. Tnfsf12 deficient mice display a more stable plaque phenotype characterized by lower lipid and macrophage content within atherosclerotic plaques. A similar phenotype was observed in diabetic mice treated with anti-TWEAK mAb. The proatherosclerotic effects of TWEAK were mediated, at least in part, by STAT1 activation and expression of proinflammatory target genes (CCL5, CXCL10 and ICAM-1), both in plaques of ApoE mice and in cultured vascular smooth muscle cells (VSMCs) under hyperglycemic conditions. Loss-of-function experiments demonstrated that TWEAK induces proinflammatory genes mRNA expression through its receptor Fn14 and STAT1 activation in cultured VSMCs. Overall, TWEAK blockade delay plaque progression and alter plaque composition in diabetic atherosclerotic mice. Therapies aimed to inhibit TWEAK expression and/or function could protect from diabetic vascular complications.

BACKGROUND AND AIMS: Circulating soluble TNF-like weak inducer of apoptosis (sTWEAK) concentrations are related to the presence of chronic kidney disease (CKD) and cardiovascular disease (CVD). However, there are no data regarding the potential association between sTWEAK and atheromatosis progression in patients free of cardiovascular events. METHODS: Soluble TWEAK serum concentration was measured in 702 CKD patients without any previous CV event from The National Observatory of Atherosclerosis in Nephrology (NEFRONA) Study. B-mode ultrasound was performed to detect the presence of carotid and/or femoral atherosclerotic plaques. The association between sTWEAK levels, atherosclerotic burden (number of plaques) and atheromatosis progression (increase in the number of plaques) after 24 months of follow-up was analyzed. RESULTS: A continuous decrease in sTWEAK concentrations, with an increase in the number of atherosclerotic plaques after 24 months of follow-up, was observed in the studied population. Multivariable linear regression analysis showed that age, blood pressure, HDL-c, and sTWEAK concentrations were independent predictors of atherosclerotic burden after 24 months of follow-up. In addition, sTWEAK concentrations diminished in CKD patients in whom progressive silent atherosclerosis was observed. Multivariable linear regression analysis showed that age, sex, smoking status and sTWEAK levels were independent predictors of atheromatosis progression after 24 months of follow-up. CONCLUSIONS: Lower sTWEAK concentrations are associated with atherosclerotic burden and atheromatosis progression in CKD patients free of clinical CVD. These data suggest that sTWEAK could serve as a biomarker to predict CV risk before clinical manifestations. This work was supported by Fondo de Investigaciones Sanitarias (Programa I3-SNS to LMBC), Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias ISCiii/FEDER PI13/00395, PI14/00384, PI16/01419, RETICS RD12/0042/0038) and Spanish Biomedical Research Centre in Cardiovascular Disease (CIBERCV) and in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain. The NEFRONA study is funded by a research grant from AbbVie and the Spanish goverment RETIC (RD12/0021/0026) and FIS PI13/01565

Patients with coronary artery disease may develop not only ischemic events but also heart failure and death due to previous myocardial damage. The purpose of this study was to test the prognostic value of a panel of plasma biomarkers related to vascular (monocyte chemoattractant protein-1 [MCP-1] and soluble tumor necrosis factor-like weak inducer of apoptosis) and myocardial damage (galectin-3, N-terminal fragment of brain natriuretic peptide [NT-proBNP], and neutrophil gelatinase-associated lipocalin) in 706 patients with chronic coronary artery disease followed for 2.2 ± 0.99 years. Secondary outcomes were the incidence of acute ischemic events (ST elevation myocardial infarction, non-ST elevation acute coronary syndrome, stroke, or transient ischemic attack) and death or heart failure. The primary outcome was the combination of the secondary outcomes. Cox proportional hazards model was used for analysis. Fifty-three patients developed acute ischemic events. Increasing MCP-1 plasma levels (p = 0.002), age, and body mass index predicted this outcome independently. Thirty-three patients developed death and/or heart failure. Galectin-3 (p = 0.007), NT-proBNP plasma levels (p = 0.004), hypertension, glomerular filtration rate, and the use of nitrates and anticoagulants were associated with this outcome independently. The development of the primary outcome was predicted independently by MCP-1 (p

High-density lipoproteins (HDLs) are complex protein and lipid assemblies whose composition is known to change in diverse pathological situations. Analysis of the HDL proteome can thus provide insight into the main mechanisms underlying abdominal aortic aneurysm (AAA) and potentially detect novel systemic biomarkers. We performed a multiplexed quantitative proteomics analysis of HDLs isolated from plasma of AAA patients (N = 14) and control study participants (N = 7). Validation was performed by western-blot (HDL), immunohistochemistry (tissue), and ELISA (plasma). HDL from AAA patients showed elevated expression of peroxiredoxin-6 (PRDX6), HLA class I histocompatibility antigen (HLA-I), retinol-binding protein 4, and paraoxonase/arylesterase 1 (PON1), whereas alpha-2 macroglobulin and C4b-binding protein were decreased. The main pathways associated with HDL alterations in AAA were oxidative stress and immune-inflammatory responses. In AAA tissue, PRDX6 colocalized with neutrophils, vascular smooth muscle cells, and lipid oxidation. Moreover, plasma PRDX6 was higher in AAA (N = 47) than in controls (N = 27), reflecting increased systemic oxidative stress. Finally, a positive correlation was recorded between PRDX6 and AAA diameter. The analysis of the HDL proteome demonstrates that redox imbalance is a major mechanism in AAA, identifying the antioxidant PRDX6 as a novel systemic biomarker of AAA. We thank Simon Bartlett for language and scientific editing. This study was supported by the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2016-80843-R, BIO2012-37926 and BIO2015-67580-P), Fondo de Investigaciones Sanitarias ISCiii-FEDER (PRB2) (IPT13/0001, ProteoRed, Redes RIC RD12/0042/00038 and RD12/0042/0056, Biobancos RD09/0076/00101 and CA12/00371), Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), and FRIAT. The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Sí

Background Soluble TWEAK (sTWEAK) and asymmetric dimethyl arginine (ADMA) concentrations have been associated with endothelial function in patients with chronic kidney disease (CKD). We tested the hypothesis that the improvement in endothelial function observed after renal transplantation is directly linked to the normalization of both sTWEAK and ADMA. Materials and methods One hundred and seventy-five kidney transplant recipients (71% men; 31·6 ± 9·4 years) were studied immediately before and on the 180th day post-transplantation. At each visit, blood samples were taken to assess circulating levels of sTWEAK and ADMA. Brachial artery endothelium-dependent vasodilatation (FMD) assessments were also performed. Results Renal transplantation was followed by an improvement in FMD. This improvement was paralleled by an increase in sTWEAK and a reduction in ADMA after transplantation (P

OBJECTIVE: To identify proteins related to intraluminal thrombus biological activities that could help to find novel pathological mechanisms and therapeutic targets for human abdominal aortic aneurysm (AAA). APPROACH AND RESULTS: Tissue-conditioned media from patients with AAA were analyzed by a mass spectrometry-based strategy using liquid chromatography coupled to tandem mass spectrometry. Global pathway analysis by Ingenuity software highlighted the presence of several circulating proteins, among them were proteins from the complement system. Complement C3 concentration and activation were assessed in plasma from AAA patients (small AAA, AAA diameter=3-5 cm and large AAA, AAA diameter >5 cm), showing decreased C3 levels and activation in large AAA patients. No association of a combination of single-nucleotide polymorphisms in complement genes between large and small AAA patients was observed. Intense extracellular C3 inmunostaining, along with C9, was observed in AAA thrombus. Analysis of C3 in AAA tissue homogenates and tissue-conditioned media showed increased levels of C3 in AAA thrombus, as well as proteolytic fragments (C3a/C3c/C3dg), suggesting its local deposition and activation. Finally, the functional role of local complement activation in polymorphonuclear (PMN) cell activation was tested, showing that C3 blockade by anti-C3 antibody was able to decrease thrombus-induced neutrophil chemotaxis and reactive oxygen species production. CONCLUSIONS: A decrease of systemic C3 concentration and activity in the later stages of AAA associated with local complement retention, consumption, and proteolysis in the thrombus could induce PMN chemotaxis and activation, playing a detrimental role in AAA progression. The article has been supported by the European Community, Fighting Aneurysmal Disease project (FP-7, HEALTH F2-2008–200647), the Spanish MICIN (SAF2010/21852), Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Red RIC (RD12/0042/00038), and biobancos (RD09/0076/00101), Fundación Lilly and Fundacion Pro Centro Nacional de Investigaciones. Sí

Abnormalities of mineral metabolism and inflammation may affect the cardiovascular system. We have assessed the relationship of left ventricular hypertrophy (LVH) with inflammation and mineral metabolism. LVH was measured in 146 outpatients with stable coronary artery disease (SCAD) using echocardiography. Calcidiol (a vitamin D metabolite), parathyroid hormone (PTH), fibroblast growth factor-23, high-sensitivity C-reactive protein, MCP-1 (monocyte chemoattractant protein-1), galectin-3, NGAL (neutrophil gelatinase-associated lipocalin), and sTWEAK (soluble TNF-related weak inducer of apoptosis) plasma levels were studied. LVH, defined as septal thickness ≥11 mm, was present in 19.9% of cases. These patients were older [75.0 (61.0-81.0) vs 64.0 (51.0-76.0) years; p=0.002], had higher prevalence of left ventricular ejection fraction (LVEF)>40%, and had higher PTH [84.7 (59.6-104.7) vs 63.2 (49.2-85.2) pg/ml; p=0.007], galectin-3 [9.6 (8.0-11.1) vs 8.3 (6.9-9.9) ng/ml; p=0.037], and NGAL (208.5±87.6 vs 173.9±73.4 ng/ml; p=0.031) plasma levels than those without LVH. Glomerular filtration rate was lower in patients with LVH than in those without it (65.1±20.0 vs 74.7±19.9 mL/min/1.73 m2; p=0.021). There were no significant differences in hypertension (79.3 vs 68.4%; p=0.363) or sex between both groups. Variables showing differences based on univariate analysis and hypertension were entered into a logistic regression analysis. Only age [odds ratio (OR) =1.052 (1.011-1.096); p=0.013], PTH plasma levels [OR=1.017 (1.003-1.031); p=0.021], and LVEF>40% [OR=7.595 (1.463-39.429); p=0.016] were independent predictors of LVH. In patients with SCAD, elevated PTH levels are independently associated with the presence of LVH. Further studies are needed to elucidate the role of PTH in the development of myocardial hypertrophy.

Essentials Abdominal aortic aneurysm (AAA) is asymptomatic and its evolution unpredictable. To find novel potential biomarkers of AAA, microvesicles are an excellent source of biomarkers. Ficolin-3 is increased in microvesicles obtained from activated platelets and AAA tissue. Increased ficolin-3 plasma levels are associated with AAA presence and progression. SummaryBackground Abdominal aortic aneurysm (AAA) patients are usually asymptomatic and AAA evolution is unpredictable. Ficolin-3, mainly synthesized by the liver, is a molecule of the lectin complement-activation pathway involved in AAA pathophysiology. Objectives To define extra-hepatic sources of ficolin-3 in AAA and investigate the role of ficolin-3 as a biomarker of the presence and progression of AAA. Methods Microvesicles (exosomes and microparticles) were isolated from culture-conditioned medium of ADP-activated platelets, as well as from AAA tissue-conditioned medium (thrombus and wall). Ficolin-3 levels were analyzed by western-blot, real-time PCR, immunohistochemistry and ELISA. Results Increased ficolin-3 levels were observed in microvesicles isolated from activated platelets. Similarly, microvesicles released from AAA tissue display increased ficolin-3 levels as compared with those from healthy tissue. Moreover, ficolin-3 mRNA levels in the AAA wall were greatly increased compared with healthy aortic walls. Immunohistochemistry of AAA tissue demonstrated increased ficolin-3, whereas little staining was present in healthy walls. Finally, increased ficolin-3 levels were observed in AAA patients’ plasma (n = 478) compared with control plasma (n = 176), which persisted after adjustment for risk factors (adjusted odds ratio [OR], 5.29; 95% confidence interval [CI], 3.27, 8.57)]. Moreover, a positive association of ficolin-3 with aortic diameter (Rho, 0.25) and need for surgical repair was observed, also after adjustment for potential confounding factors (adjusted hazard ratio, 1.55; 95% CI, 1.11, 2.15). Conclusions In addition to its hepatic expression, ficolin-3 may be released into the extracellular medium via microvesicles, by both activated cells and pathological AAA tissue. Ficolin-3 plasma levels are associated with the presence and progression of AAA, suggesting its potential role as a biomarker of AAA.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background and Objectives We investigated the relationship of the Syntax Score (SS) and coronary artery calcification (CAC), with plasma levels of biomarkers related to cardiovascular damage and mineral metabolism, as there is sparse information in this field. Methods We studied 270 patients with coronary disease that had an acute coronary syndrome (ACS) six months before. Calcidiol, fibroblast growth factor-23, parathormone, phosphate and monocyte chemoattractant protein-1 [MCP-1], high-sensitivity C-reactive protein, galectin-3, and N-terminal pro-brain natriuretic peptide [NT-proBNP] levels, among other biomarkers, were determined. CAC was assessed by coronary angiogram as low-grade (0-1) and high-grade (2-3) calcification, measured with a semiquantitative scale ranging from 0 (none) to 3 (severe). For the SS study patients were divided in SS, This work was supported by grants from Fondo de Investigaciones Sanitarias [PI14/1567, PI14/00386, PIE13/00051], Spanish Society of Cardiology; Spanish Heart Foundation; Instituto de Salud Carlos III FEDER [FJD biobank grant RD09/0076/00101]; and AbbVie Laboratories

BACKGROUND Patients with coronary heart disease (CHD) without classical cardiovascular risk factors (CRF) are uncommon, and their profile has not been thoroughly studied. In CHD patients, we have assessed the differences in several biomarkers between those with and without CRF. METHODS We studied 704 patients with CHD, analyzing plasma levels of biomarkers related to inflammation, thrombosis, renal damage, and heart failure: hs-CRP (high-sensitivity C-reactive protein), MCP-1 (monocyte chemoattractant protein-1), galectin-3, NT-pro-BNP (N-terminal fragment of brain natriuretic peptide), calcidiol (vitamin D metabolite), fibroblast growth factor-23 (FGF-23), parathormone, and phosphate. RESULTS Twenty patients (2.8%) exhibited no CRFs. Clinical variables were well balanced in both groups, with the logical exceptions of no use of antidiabetic drugs, lower triglyceride and glucose, and higher high-density lipoprotein cholesterol in no-CRF patients. No-CRF patients showed lower hs-CRP (2.574±3.120 vs 4.554±9.786 mg/L; P=0.018), MCP-1 (114.75±36.29 vs 143.56±65.37 pg/ml; P=0.003) and FGF-23 (79.28±40.22 vs 105.17±156.61 RU/ml; P=0.024) and higher calcidiol (23.66±9.12 vs 19.49±8.18 ng/ml; P=0.025) levels. At follow-up, 10.0% vs 11.0% patients experienced acute ischemic event, heart failure, or death in the non-CRF and CRF groups, respectively (P=0.815, log-rank test). The limited number of non-CRF patients may have influenced this finding. A Cox regression analysis in the whole population showed that high calcidiol, and low MCP-1 and FGF-23 plasma levels are associated to a better prognosis. CONCLUSIONS CHD patients without CRFs show a favorable biomarker profile in terms of inflammation and mineral metabolism. Further studies are needed to investigate whether this difference translates into a better prognosis., This work was supported by grants from Fondo de Investigaciones Sanitarias (PI05/0451, PI05/1497, PI05/52475, PI05/1043, PS09/01405, and PI10/00072); Spanish Society of Cardiology; Spanish Heart Foundation; Spanish Society of Arteriosclerosis; RECAVA (RD06/0014/0035); Fundación Lilly; Instituto de Salud Carlos III FEDER (FJD Biobank: RD09/0076/00101); and AbbVie Laboratories

Background: Macroscopic hematuria (MH) may cause acute kidney injury (AKI) in IgA nephropathy. Up to 25% of patients with MH-associated AKI do not recover baseline renal function. Our objective was to identify subjects at high risk for an adverse renal function. Methods: We examined macrophages, oxidative stress markers (NADPH-p22 and HO-1) and the hemoglobin scavenger receptor (CD163) in renal biopsy specimens from 33 MH-AKI patients with complete recovery (CR, n = 17) or incomplete recovery (IR, n = 16) of renal function after 6.72 (range 0.5–21.5) years of follow-up. Results: CD163-expressing macrophages, HO-1 and NADPH-p22 expression were located in areas surrounding tubules with iron deposits and filled with erythrocyte casts. CD163-positive macrophages score and HO-1- and p22-positive staining correlated positively with percentage of tubules with erythrocyte casts and tubular necrosis. Macrophage infiltration, CD163-positive macrophage score, NADPH-p22- and HO-1-positive staining areas were significantly greater in IR patients when compared with CR patients. The CD163-positive macrophage score and oxidative stress markers (p22 and HO-1) were negatively correlated with renal function outcome, as determined by estimated glomerular filtration rate (eGFR) and proteinuria, at the end of the follow-up period. In multivariate analysis, the CD163-positive macrophage score remained significantly associated with final eGFR and proteinuria after adjustment by age, gender, duration of MH, initial eGFR and proteinuria. Conclusions: Increased macrophage infiltration, CD163 expression and oxidative stress are significant prognostic factors for an IR of renal function in patients with MH-associated AKI. These molecular pathways may be involved in the renal response to injury and could be useful to improve diagnosis and therapeutics.

Aim Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has recently been introduced as a potential mediator of cardiovascular disease. We examined the associations between sTWEAK, its scavenger receptor sCD163, sCD163/sTWEAK ratio and risk for long-term all-cause and cardiovascular mortality in patients with lower-extremity peripheral arterial disease (PAD). Methods sTWEAK and sCD163 serum levels were measured retrospectively in a cohort of 295 patients with symptomatic PAD followed for 6.1 ± 2.1 years. The endpoints were defined as all-cause or cardiovascular death. The relationship between sTWEAK, sCD163 levels, sCD163/sTWEAK ratio, and times to fatal outcome was examined by Cox proportional hazards analysis. Results sTWEAK levels were significantly lower (672 (IQR 515; 872) pg/ml vs. 814 (IQR 673; 957) pg/ml, p

Background and objectives: Soluble TNF-like weak inducer of apoptosis (sTWEAK) and long pentraxin-3 (PTX3) concentrations have been associated with endothelial function in patients with chronic kidney disease (CKD). This study tested the hypothesis that the improvement in endothelial function after initiation of angiotensin II receptor blocker (valsartan), calcium channel blocker (amlodipine) therapy, or a combination of both is directly linked to the normalization of sTWEAK and PTX3. Design, setting, participants, & measurements: One-hundred-eight diabetic CKD stage I patients with hypertension (56% men, 46.7 ± 5.3 years) were allocated to a 12-week intervention with amlodipine (10 mg/d), valsartan (160 mg/d), or their combination. Plasma levels of sTWEAK, PTX3, and flow-mediated dilation (FMD) were studied during the interventions. Results: All treatment strategies effectively increased FMD and reduced proteinuria, confirming a more prone reduction with the combined therapy. These improvements were followed by significant PTX3 reductions. Valsartan alone and in combination with amlodipine achieved significant incremental raises in sTWEAK plasma levels. More importantly, the changes observed in sTWEAK (β = 0.25, P = 0.006) or PTX3 (β = −0.24, P = 0.007) plasma levels were independently associated with the improvement in ultrasonographically measured FMD. Conclusions: This study shows that treatment with antihypertensive drugs improves FMD and normalizes proteinuria, PTX3, and sTWEAK in diabetic CKD stage I patients with hypertension. The improvement in FMD was independently associated with PTX3 and sTWEAK normalization. Two surrogate biomarkers of endothelial function are therefore identified with potential as therapeutic targets. The study was registered in clinicaltrials.gov as NCT00921570.

Objective—In addition to its role in the clearance of haptoglobin-hemoglobin (Hp-Hb) complexes, CD163 is a macrophage scavenger receptor for tumor necrosis factor–like weak inducer of apoptosis (TWEAK). We recently reported that the CD163/TWEAK plasma ratio could be a potential biomarker of atherothrombosis in asymptomatic subjects. In this study, we assessed soluble TWEAK (sTWEAK) and soluble CD163 (sCD163) plasma levels in white males with peripheral artery disease (PAD) and in atherothrombotic femoral plaques to evaluate their relationship with disease. We also analyzed whether Hp-Hb complexes could compete for CD163-mediated TWEAK uptake.Methods and Results—Patients with PAD (n=155) showed a trend toward lower sTWEAK (median [interquartile range]: 134 [110–204] versus 147 [119–205] pg/mL;P=0.067) and higher sCD163 (median [interquartile range]: 367 [269–506] versus 288 [234–369] ng/mL;PP=0.049). Analysis of conditioned medium obtained from cultured human atherothrombotic femoral plaque samples (n=36) and healthy aortas (n=14) revealed that high amounts of sCD163 were released by the atherothrombotic tissue, whereas sTWEAK presented the opposite trend (PConclusion—Our results suggest that the sCD163/sTWEAK plasma ratio may be associated with atherothrombosis burden in PAD. We hypothesize that an imbalance between TWEAK and CD163 could reflect the progression of atherothrombosis.

Aims Heat shock protein 90 (HSP90) is a ubiquitous chaperone involved in the folding, activation, and assembly of many proteins. HSP90 inhibitors [17-allylamino-17-demethoxygeldamycin (17-AAG)/17-dimethyl aminothylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG)] bind to and inactivate HSP90, increasing the heat shock response and suppressing different signalling pathways. We aim to investigate the effect of HSP90 inhibitors in the modulation of inflammatory responses during atherogenesis. Methods and results In human atherosclerotic plaques, HSP90 immunostaining was increased in inflammatory regions and in plaques characterized by lower cap thickness. In cultured human macrophages and vascular smooth muscle cells, treatment with either 17-AAG or 17-DMAG increased HSP70 expression and reduced transcription factor [signal transducers and activators of transcription (STAT) and nuclear factor-κB (NF-κB)] activation and chemokine expression induced by proinflammatory cytokines. In vivo , hyperlipidaemic ApoE−/− mice were randomized to 17-DMAG (2 mg/kg every 2 days, n = 11) or vehicle injected ( n = 9) during 10 weeks. Atherosclerotic plaques of mice treated with 17-DMAG displayed increased HSP70 expression and diminished NF-κB and STAT activation, along with decreased lesion, lipid, and macrophage content, compared with vehicle-injected mice. In addition, treatment with 17-DMAG significantly reduced monocyte chemoattractant protein-1 levels, both in plaques and in plasma. Conclusion HSP90 expression is associated with features of plaque instability in advanced human lesions. HSP90 inhibitors reduce inflammatory responses in atherosclerosis, suggesting that HSP90 could be a novel therapeutic target in atherosclerosis.