RESUMEN
Background: Chronic obstructive pulmonary disease (COPD), usually caused by long-term tobacco smoking, is independently associated with systemic inflammation. However, little is known about the systemic inflammatory status of patients with early-stage COPD (classified as GOLD 1) and long-term smokers with normal lung function (LF). Here, we characterised the early changes in the associated inflammatory state in patients with GOLD 1 and in long-term smokers with normal LF. Methods: Fresh blood samples from 27 patients with GOLD 1, 27 long-term smokers and 14 non-smokers were analysed. Results: Ex vivo blood analysis revealed greater leucocyte-platelet adhesion to TNFα-stimulated pulmonary endothelium in patients with GOLD 1 than in smokers and non-smokers. In addition, platelet reactivity (platelet count and activation, and fibrinogen levels) and the frequency of leucocyte-platelet aggregates were higher in the GOLD 1 group than in the other groups. Some of these findings correlated with the severity of lung dysfunction, while platelet hyperactivity correlated positively with leucocyte-platelet adhesion. The GOLD 1 group also had a higher Th17/Treg ratio and higher circulating levels of IL-17C and C-reactive protein than the other groups. However, long-term smokers also had higher leucocyte counts and activation, and higher plasma levels of TNFα and IL-6 than non-smokers. Conclusion: Our data suggest that the altered inflammatory parameters in long-term smokers may represent early biomarkers of COPD. Accordingly, peripheral immune monitoring based on the above parameters may be useful to prevent disease progression in long-term smokers with normal LF and early COPD.
Asunto(s)
Plaquetas , Leucocitos , Activación Plaquetaria , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Masculino , Femenino , Persona de Mediana Edad , Leucocitos/inmunología , Leucocitos/metabolismo , Plaquetas/metabolismo , Plaquetas/inmunología , Anciano , Adhesión Celular , Fumar/efectos adversos , Biomarcadores/sangreRESUMEN
BACKGROUND: Renal cell carcinoma (RCC) is the third most frequent urological neoplasia. Proper risk stratification is essential for adequate management. Various calculators are available. This project aims to evaluate the accuracy of the calculators applied to our patients. METHODS: We performed a retrospective study of the nephrectomies due to RCC performed from January 2008 to December 2013. We applied the most widely used predictive models (University of California, Los Angeles Integrated Staging System (UISS), Stage, Size, Grade and Necrosis (SSIGN), Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic RCC Database Consortium (IMDC)) to stratify patients in different risk groups. We evaluated progression-free survival (PFS) or death caused by RCC (cancer-specific survival (CSS)) or other causes (overall survival (OS)). RESULTS: We analysed 238 patients. The 5-year OS, CSS and PFS were 76%, 85% and 83%, whereas the 10-year OS, CSS and PFS were 47%, 75% and 77%, respectively. The 5-year survival analysis by risk groups according to the prognostic models showed that the PFS was 0% and 20.4% in high- and intermediate-risk metastatic RCC (mRCC). Moreover, the PFS was 90%, 95.2% and 98.9% in localised high-, intermediate- and low-risk RCC according to the UISS (area under the receiver operating characteristics curve (AUC): 0.93). The SSIGN model showed a CSS of 99% for the group with the lowest score and 5.3% for the group with the worst prognosis (AUC: 0.91). The OS of mRCC showed medians of 13.25 and 87 months according to MSKCC (AUC: 0.75) and 16, 23 and 85 months according to IMDC (AUC: 0.71) (high risk, intermediate and low). CONCLUSIONS: The validation of the predictive models carried out with our patients showed consistency in many of the results. Risk stratification should be implemented.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Centros de Atención Terciaria , Humanos , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/mortalidad , Estudios Retrospectivos , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Anciano , Medición de Riesgo , Nefrectomía , Adulto , Anciano de 80 o más AñosRESUMEN
Introducción y objetivo: la fístula entre la arteria ilíaca y el conducto ileal (Bricker) es una patología con un elevado riesgo vital. El objetivo de este artículo es dar a conocer esta entidad, describir su presentación, sus métodos diagnósticos y su tratamiento basados en los casos en un hospital terciario y en la revisión de la literatura. Material y métodos: presentamos los casos de fístulas arterioileales ocurridos en nuestro centro entre 2016 y 2020. Se realizó una exhaustiva revisión de la literatura publicada hasta la fecha mediante la búsqueda en PubMed de artículos publicados entre 1971 y 2020, incluyendo las palabras claves arterial ileal conduit fistula y seleccionando únicamente los artículos en español e inglés. Resultados: se identificaron 4 casos en nuestro centro. Se reconocieron en la búsqueda bibliográfica 13 artículos que describían 16 casos de fístulas arterioileales. La mayoría compartía factores comunes de riesgo y el abordaje quirúrgico fue mayoritariamente la cirugía abierta. El abordaje adecuado parece ser la combinación de cirugía abierta y endovascular, efectiva en 3 de nuestros 4 casos. Conclusión: la fístula entre la arteria ilíaca y el conducto ileal es una complicación infrecuente y grave, con una mortalidad en torno al 44 %. Resulta difícil de diagnosticar, salvo que exista alta sospecha clínica, con pocos casos descritos en la literatura. Es fundamental tener en cuenta la historia clínica previa del paciente. (AU)
Introduction and objective: the presence of a fistula between the iliac artery and the ileal conduit is a live-threatening condition that must be known and, therefore, suspected after a massive bleeding through the ileal conduit. The objective of this article is to present the arterial-ileal fistula, describe its presentation, diagnostic methods, and treatments, based on the cases presented in a tertiary referral center and literature review. Material and methods: all cases of arterial-ileal fistulas collected at our center from 2016 through 2020 are presented here. A comprehensive literature review published to date was also conducted based on a search for articles published from 1971 through 2020 on the PubMed database with the keywords arterial ileal conduit fistula, including studies only published in English and Spanish languages. Results: a total of 4 cases were identified in our center. A total of 13 articles describing 16 cases of arterial-ileal fistula were identified from the medical literature, most of them with some risk factors in common. The approach followed was mainly open surgery. The proper treatment seems to be a combination between open surgery and endovascular approaches, which turned out to be effective in 3 of our 4 cases. Conclusion: a fistula between the artery and the ileal conduit is a rare but serious complication, with a 44% mortality rate. It is difficult to diagnose unless there is clinical suspicion involved, with only a few cases reported in the medical literature. We should consider the patients pathological history to identify this entity. (AU)
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Anciano , Fístula Arterio-Arterial , HematuriaRESUMEN
Antineoplastic therapies for prostate cancer (PCa) have traditionally centered around the androgen receptor (AR) pathway, which has demonstrated a significant role in oncogenesis. Nevertheless, it is becoming progressively apparent that therapeutic strategies must diversify their focus due to the emergence of resistance mechanisms that the tumor employs when subjected to monomolecular treatments. This review illustrates how the dysregulation of the lipid metabolic pathway constitutes a survival strategy adopted by tumors to evade eradication efforts. Integrating this aspect into oncological management could prove valuable in combating PCa.
Asunto(s)
Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/patología , Ácido Mevalónico , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Cardiovascular disease (CVD) remains the leading cause of death and disability worldwide. While many factors can contribute to CVD, atherosclerosis is the cardinal underlying pathology, and its development is associated with several metabolic risk factors including dyslipidemia and obesity. Recent studies have definitively demonstrated a link between low-grade systemic inflammation and two relevant metabolic abnormalities: hypercholesterolemia and obesity. Interestingly, both metabolic disorders are also associated with endothelial dysfunction/activation, a proinflammatory and prothrombotic phenotype of the endothelium that involves leukocyte infiltration into the arterial wall, one of the earliest stages of atherogenesis. This article reviews the current literature on the intricate relationship between hypercholesterolemia and obesity and the associated systemic inflammation and endothelial dysfunction, and discusses the effectiveness of present, emerging and in-development pharmacological therapies used to treat these metabolic disorders with a focus on their effects on the associated systemic inflammatory state and cardiovascular risk.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Hipercolesterolemia , Hiperlipidemias , Humanos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/etiología , Hipercolesterolemia/complicaciones , Inflamación/complicaciones , Obesidad/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , Aterosclerosis/complicacionesRESUMEN
BACKGROUND CONTEXT: Intervertebral disc degeneration (IVDD) is an incurable, specific treatment-orphan disease with an increasing burden worldwide. Although great efforts have been made to develop new regenerative therapies, their clinical success is limited. PURPOSE: Characterize the metabolomic and gene expression changes underpinning human disc degeneration. This study also aimed to disclose new molecular targets for developing and optimizing novel biological approaches for IVDD. STUDY DESIGN: Intervertebral disc cells were obtained from IVDD patients undergoing circumferential arthrodesis surgery or from healthy subjects. Mimicking the harmful microenvironment of degenerated discs, cells isolated from the nucleus pulposus (NP) and annulus fibrosus (AF) were exposed to the proinflammatory cytokine IL-1ß and the adipokine leptin. The metabolomic signature and molecular profile of human disc cells were unraveled for the first time. METHODS: The metabolomic and lipidomic profiles of IVDD and healthy disc cells were analyzed by high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Gene expression was investigated by SYBR green-based quantitative real-time RT-PCR. Altered metabolites and gene expression were documented. RESULTS: Lipidomic analysis revealed decreased levels of triacylglycerols (TG), diacylglycerol (DG), fatty acids (FA), phosphatidylcholine (PC), lysophosphatidylinositols (LPI) and sphingomyelin (SM), and increased levels of bile acids (BA) and ceramides, likely promoting disc cell metabolism changing from glycolysis to fatty acid oxidation and following cell death. The gene expression profile of disc cells suggests LCN2 and LEAP2/GHRL as promising molecular therapeutic targets for disc degeneration and demonstrates the expression of genes related to inflammation (NOS2, COX2, IL-6, IL-8, IL-1ß, and TNF-α) or encoding adipokines (PGRN, NAMPT, NUCB2, SERPINE2, and RARRES2), matrix metalloproteinases (MMP9 and MMP13), and vascular adhesion molecules (VCAM1). CONCLUSIONS: Altogether, the presented results disclose the NP and AF cell biology changes from healthy to degenerated discs, allowing the identification of promising molecular therapeutic targets for intervertebral disc degeneration. CLINICAL SIGNIFICANCE: Our results are relevant to improving current biological-based strategies aiming to repair IVD by restoring cellular lipid metabolites as well as adipokines homeostasis. Ultimately, our results will be valuable for successful, long-lasting relief of painful IVDD.
Asunto(s)
Anillo Fibroso , Degeneración del Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Humanos , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/metabolismo , Serpina E2/metabolismo , Disco Intervertebral/metabolismo , Anillo Fibroso/metabolismo , Núcleo Pulposo/metabolismo , Adipoquinas/metabolismoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent chronic liver disease in Western countries, affecting approximately 25% of the adult population. This condition encompasses a spectrum of liver diseases characterized by abnormal accumulation of fat in liver tissue (non-alcoholic fatty liver, NAFL) that can progress to non-alcoholic steatohepatitis (NASH), characterized by the presence of liver inflammation and damage. The latter form often coexists with liver fibrosis which, in turn, may progress to a state of cirrhosis and, potentially, hepatocarcinoma, both irreversible processes that often lead to the patient's death and/or the need for liver transplantation. Along with the high associated economic burden, the high mortality rate among NAFLD patients raises interest, not only in the search for novel therapeutic approaches, but also in early diagnosis and prevention to reduce the incidence of NAFLD-related complications. In this line, an exhaustive characterization of the immune status of patients with NAFLD is mandatory. Herein, we attempted to gather and compare the current and relevant scientific evidence on this matter, mainly on human reports. We addressed the current knowledge related to circulating cellular and soluble mediators, particularly platelets, different leukocyte subsets and relevant inflammatory soluble mediators.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Adulto , Humanos , Inflamación/patología , Hígado/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológicoRESUMEN
PURPOSE: To analyze the variability, associated actors, and the design of nomograms for individualized testosterone recovery after cessation of androgen deprivation therapy (ADT). MATERIALS AND METHODS: A longitudinal study was carried out with 208 patients in the period 2003 to 2019. Castrated and normogonadic testosterone levels were defined as 0.5 and 3.5 ng/mL, respectively. The cumulative incidence curve described the recovery of testosterone. Univariate and multivariate analyzes were performed to predict testosterone recovery with candidate prognostic factors prostate-specific antigen at diagnosis, clinical stage, Gleason score from biopsy, age at cessation of ADT, duration of ADT, primary therapy and use of LHRH (luteinizing hormone-releasing hormone) agonists. RESULTS: The median follow-up duration in the study was 80 months (interquartile range, 49-99 mo). Twenty-five percent and 81% of patients did not recover the castrate and normogonadic levels, respectively. Duration of ADT and age at ADT cessation were significant predictors of testosterone recovery. We built two nomograms for testosterone recovery at 12, 24, 36, and 60 months. The castration recovery model had good calibration. The C-index was 0.677, with area under the receiver operating characteristic curve (AUC-ROC) of 0.736, 0.783, 0.782, and 0.780 at 12, 24, 36, and 60 months, respectively. The normogonadic recovery model overestimated the higher values of probability of recovery. The Cindex was 0.683, with AUC values of 0.812, 0.711, 0.708 and 0.693 at 12, 24, 36, and 60 months, respectively. CONCLUSIONS: Depending on the age of the patient and the length of treatment, clinicians may stop ADT and the castrated testosterone level will be maintained or, if the course of treatment has been short, we can estimate if it will return to normogonadic levels.
RESUMEN
BACKGROUND AND PURPOSE: Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPARα agonists on glucose metabolism and the adverse effects associated with selective PPARγ activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements. EXPERIMENTAL APPROACH: BP-2 was used in transactivation assays to evaluate its agonism to PPARα, PPARß/δ and PPARγ. A parallel-plate flow chamber was employed to investigate its effect on TNFα-induced leukocyte-endothelium interactions. Flow cytometry and immunofluorescence were used to determine its effects on the expression of endothelial cell adhesion molecules (CAMs) and chemokines and p38-MAPK/NF-κB activation. PPARs/RXRα interactions were determined using a gene silencing approach. Analysis of its impact on metabolic abnormalities and inflammation was performed in ob/ob mice. KEY RESULTS: BP-2 displayed strong PPARα activity, with moderate and weak activity against PPARß/δ and PPARγ, respectively. In vitro, BP-2 reduced TNFα-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX3CL1 expression, suppressed mononuclear cell arrest via PPARß/δ-RXRα interactions and decreased p38-MAPK/NF-κB activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed T-lymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206. CONCLUSION AND IMPLICATIONS: BP-2 emerges as a novel pan-PPAR lead candidate to normalize glycemia/triglyceridemia and minimize inflammation in metabolic disorders, likely preventing the development of further cardiovascular complications.
Asunto(s)
Enfermedades Metabólicas , PPAR delta , PPAR-beta , Ratones , Animales , PPAR gamma/metabolismo , PPAR alfa/metabolismo , PPAR-beta/metabolismo , Factor de Necrosis Tumoral alfa , Benzopiranos , FN-kappa B , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológicoRESUMEN
OBJECTIVE: The diagnosis of type 1 diabetes mellitus (DM1) has a major impact on young people and their families. Psychosocial factors, patient motivation, participation and acceptance of the disease are essential to achieve good blood glucose control. Our aims were to analyse personality traits and how they are related to blood glucose control in patients with DM1. METHODS: Sixty-two patients with DM1 over 18 years of age, with at least one-year disease duration and absence of advanced chronic complications were studied. Clinical, biological and personality parameters were measured. The Millon Index of Personality Styles was administered for personality assessment. RESULTS: Significant correlations between different personality variables and glycated haemoglobin (HbA1c) values were found. Individuals with poor blood glucose control had significantly higher scores on the Feeling-guided (53.6±25.7 vs 36.2±26.8, p=0.021), Innovation-seeking (36.7±24.1 vs 21.9±21.4, p=0.025), Dissenting (41.1±24.4 vs 15.6±16.6, p=0.001), Submissive (41.5±25.1 vs 28.3±14.7, p=0.038) and Dissatisfied (37.5±27.5 vs 19.5±20.2, p=0.015) scales. This psychological profile is characterised by greater focus on emotions and personal values (feeling-guided), the tendency to reject conventional ideas (innovation-seeking), an aversion to complying with norms and a preference for autonomy (unconventional/dissenting), labile self-confidence (submissive/yielding) and expressed disagreement with others (dissatisfied/complaining). Factor analysis based on the main components of the variance yielded four factors. Factor characterised as related to rebelliousness or independent judgement and action was correlated with poor blood glucose control (r=0.402, p<0.05). CONCLUSION: The rebellious or non-conformist personality type is closely associated with poor blood glucose control in patients with DM1.
Asunto(s)
Diabetes Mellitus Tipo 1 , Humanos , Adolescente , Adulto , Control Glucémico , Hemoglobina Glucada/análisis , PersonalidadRESUMEN
Non-alcoholic fatty liver disease (NAFLD) has become the major cause of chronic hepatic illness and the leading indication for liver transplantation in the future decades. NAFLD is also commonly associated with other high-incident non-communicable diseases, such as cardiovascular complications, type 2 diabetes, and chronic kidney disease. Aggravating the socio-economic impact of this complex pathology, routinely feasible diagnostic methodologies and effective drugs for NAFLD management are unavailable. The pathophysiology of NAFLD, recently defined as metabolic associated fatty liver disease (MAFLD), is correlated with abnormal adipose tissue-liver axis communication because obesity-associated white adipose tissue (WAT) inflammation and metabolic dysfunction prompt hepatic insulin resistance (IR), lipid accumulation (steatosis), non-alcoholic steatohepatitis (NASH), and fibrosis. Accumulating evidence links adipokines, cytokine-like hormones secreted by adipose tissue that have immunometabolic activity, with NAFLD pathogenesis and progression; however, much uncertainty still exists. Here, the current knowledge on the roles of leptin, adiponectin, ghrelin, resistin, retinol-binding protein 4 (RBP4), visfatin, chemerin, and adipocyte fatty-acid-binding protein (AFABP) in NAFLD, taken from preclinical to clinical studies, is overviewed. The effect of therapeutic interventions on adipokines' circulating levels are also covered. Finally, future directions to address the potential of adipokines as therapeutic targets and disease biomarkers for NAFLD are discussed.
RESUMEN
Background: Coronavirus disease 2019 (COVID-19) has placed enormous pressure on intensive care units (ICUs) and on healthcare systems in general. A deeper understanding of the pathophysiology of the most severe forms of COVID-19 would help guide the development of more effective interventions. Herein, we characterized the inflammatory state of patients with COVID-19 of varying degrees of severity to identify admission biomarkers for predicting COVID-19 worsening. Design: Admission blood samples were obtained from 78 patients with COVID-19. Radiographic assessment of lung edema (RALE) scoring was calculated by imaging. Platelet and leukocyte counts were measured by flow cytometry, and plasma levels of C-reactive protein were assessed by immunoturbidimetry, and interleukin (IL)-8/CXCL8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and monocyte chemoattractant protein-1 (MCP-1/CCL2) levels by enzyme-linked immunosorbent assay (ELISA). Results: The RALE score correlated with several admission hemogram (platelets, neutrophils, and lymphocytes) and inflammatory (IL-8/CXCL8, MCP-1/CCL2, IL-10, and C-reactive protein) parameters. COVID-19 worsening, based on the need for oxygen (Δoxygen supply) during hospitalization, correlated negatively with admission lymphocyte counts but positively with neutrophil-to-lymphocyte ratio and with plasma levels of the inflammatory parameters correlating with RALE score. Conclusion: Our data indicate a correlation between the RALE score and Δoxygen supply and admission inflammatory status. The identification of a panel of biomarkers that reflect COVID severity might be useful to predict disease worsening during hospitalization and to guide clinical management of COVID-19-related complications. Finally, therapies targeting IL-8/CXCL8- or IL-10 activity may offer therapeutic approaches in COVID-19 treatment.
RESUMEN
Sphingosine kinase (SphK), which catalyzes the transfer of phosphate from ATP to sphingosine (Sph) generating sphingosine-1-phosphate (S1P) has emerged as therapeutic target since the discovery of connections of S1P with cancer progress. So far, most effort has focused on the development of inhibitors of SphK1, and selective inhibitors of SphK2 have been much less explored. Here, we describe the syntheses of new sphingosine derivatives bearing a tetrasubstituted carbon atom at C-2, dimethylhydrazino or azo moieties in the polar head, and alkane, alkene or alkyne moieties as linkers between the polar ahead and the fatty tail. In vitro inhibitory assays based on a time resolved fluorescence energy transfer (TR-FRET) have revealed the hydrazino and alkynyl moieties as the best combination for the design of selective SphK2 inhibitors (19a and 19b). Docking studies showed that compounds 19a-b have the optimal binding to SphK2 through the exploitation of polar but also hydrophobic interactions of their head group with the head of the enzyme binding pocket, while also producing full contact of the fatty tail with the hydrophobic pocket of the enzyme. By contrast, this elongation causes loss of contact surface with the shorter hydrophobic toe of the SphK1 isoform, thus accounting for the SphK2-biased selectivity of these compounds. Cell viability assays of the most promising candidates 19a-b have shown that 19a is not cytotoxic to human endothelial cells at 30 µM.
Asunto(s)
Antineoplásicos , Esfingosina , Antineoplásicos/farmacología , Células Endoteliales/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Fosfotransferasas (Aceptor de Grupo Alcohol)RESUMEN
En diciembre de 2019, apareció un nuevo coronavirus que ha dado lugar a una pandemia. Dadas las características del paciente trasplantado, se hace necesario conocer cuál ha sido la repercusión respecto a la infección por SARS-CoV-2, planteándonos como objetivo describir la incidencia de SARS-CoV-2 en pacientes con un trasplante renal.Se llevó a cabo un estudio observacional de cohorte retrospectiva de pacientes con un trasplante renal y que están en seguimiento por la consulta de trasplantes de un hospital terciario, durante el periodo comprendido entre el 1 de marzo de 2020 y el 1 de marzo de 2021. Se incluyeron 604 individuos, con una edad media de 61,6±12,8 años. Un 62,3% (n=376) fueron hombres. La incidencia por SARS-CoV-2 fue 14,9% (n=90). La mortalidad por SARS-CoV-2 fue 3,8% (n=23) lo que supone una letalidad del 25,5%. Al comparar si han pasado la infección en función del sexo no se encontraron diferencias significativas. Tampoco al comparar en función de la edad media, que fue de 60,9±11,8 años en los infectados y de 61,7±12,9 años en los no infectados. Se encontraron diferencias significativas (p=0,005) al comparar la media de años transcurridos desde el trasplante; que fue de 8,7±5,6 años en los infectados y de 11 ±7,3 años en los no infectados.La incidencia de infección por SARS-CoV-2 encontrada en personas con TR fue muy superior a la descrita para la población general. La letalidad y la mortalidad también fueron mayores que en la población general, pero acordes con otras poblaciones de individuos con TR. (AU)
In December 2019, a new coronavirus appeared and generated a pandemic. Considering the characteristics of the transplanted patient, it is relevant to know the impact regarding SARS-CoV-2 infection, aiming to describe the incidence of SARS-CoV-2 in renal transplant patients.A retrospective observational cohort study of patients with a renal transplant and under follow-up by the transplant clinic of a tertiary hospital was conducted during the period from 1 March 2020 to 1 March 2021. A total of 604 individuals were included, with a mean age of 61.6 ±12.8 years. 62.3% (n=376) were men.SARS-CoV-2 incidence was 14.9% (n=90). Mortality due to SARS-CoV-2 was 3.8% (n=23), giving a case fatality of 25.5%. No significant differences were found according to sex and age, being 60.9±11.8 years in those infected and 61.7±12.9 years in those not infected. Significant differences (p=0.005) were found for the mean number of years since transplantation; 8.7±5.6 years in those infected and 11±7.3 years in those not infected.The incidence of SARS-CoV-2 infection in renal transplant recipients was much higher than that described for the general population. Case fatality and mortality were also higher than in the general population, but in line with other series of individuals with renal transplantation. (AU)
Asunto(s)
Humanos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Pandemias , Trasplante de Riñón , Infecciones por Coronavirus , Mortalidad , Pacientes , HospitalesRESUMEN
BACKGROUND AND AIMS: Obesity is a key contributing factor to incidental type 2 diabetes and cardiovascular disease. CXCR3 receptor and its ligands CXCL 10 and 11 are associated with atherosclerosis and cardiovascular disease. The aim of our study was to analyse the role of the CXCR3 ligands on insulin resistance (IR) and endothelial dysfunction in human obesity. METHODS AND RESULTS: We have studied 45 obese patients (mean age 44 ± 6 years, body mass index 45 ± 9 kg/m2) who were selected for Roux-Y-gastric bypass surgery and 21 non obese control subjects with similar age and gender distribution. We measured by ELISA the circulating levels of the CXCR3 ligands interferon-γ inducible protein 10 (IP-10/CXCL10) and interferon-γ-inducible T-cell alpha chemoattractant (I-TAC/CXCL11). Using an ex vivo procedure with the flow chamber assay, we have investigated the effect of such chemokines on endothelial leukocytes arrest under dynamic conditions. Peripheral blood levels of CXCL10 and CXCL11 were significantly higher in obese subjects than in controls (p < 0.001) and significantly correlated with BMI, waist circunference and HOMA-IR. Obese patients with HOMA-IR index above 75th percentile showed highest increase of circulating CXCL10 and CXCL11 values. Under dynamic flow conditions, the enhanced adhesion of patient leukocytes to TNFα-induced human arterial endothelial cells was partly dependent on CXCR3. CONCLUSIONS: The study demonstrates that CXCL10 and CXCL11 are associated with IR and enhance leukocyte endothelial arrest in obese subjects. Blockade of CXCR3 signaling might be a new therapeutic approach for the prevention of obesity-associated cardiovascular co-morbidities.
Asunto(s)
Adhesión Celular , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/metabolismo , Células Endoteliales/metabolismo , Resistencia a la Insulina , Leucocitos/metabolismo , Obesidad/metabolismo , Adulto , Estudios de Casos y Controles , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Femenino , Humanos , Leucocitos/patología , Masculino , Persona de Mediana Edad , Obesidad/patología , Obesidad/fisiopatología , Receptores CXCR3/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia ArribaRESUMEN
Familial hypercholesterolemia (FH) is associated with low-grade systemic inflammation, a key driver of premature atherosclerosis. We investigated the effects of inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) function on inflammatory state, endothelial dysfunction and cardiovascular outcomes in patients with FH. Fourteen patients with FH were evaluated before and 8 weeks after administration of a PCSK9 blocking monoclonal antibody (alirocumab, 150â¯mg/subcutaneous/14 days). In vivo and ex vivo analysis revealed that alirocumab blunted the attachment of leukocytes to TNFα-stimulated human umbilical arterial endothelial cells (HUAEC) and suppressed the activation of platelets and most leukocyte subsets, which was accompanied by the diminished expression of CX3CR1, CXCR6 and CCR2 on several leukocyte subpopulations. By contrast, T-regulatory cell activation was enhanced by alirocumab treatment, which also elevated anti-inflammatory IL-10 plasma levels and lowered circulating pro-inflammatory cytokines. Plasma levels of IFNγ positively correlated with levels of total and LDL-cholesterol, whereas circulating IL-10 levels negatively correlated with these key lipid parameters. In vitro analysis revealed that TNFα stimulation of HUAEC increased the expression of PCSK9, whereas endothelial PCSK9 silencing reduced TNFα-induced mononuclear cell adhesion mediated by Nox5 up-regulation and p38-MAPK/NFκB activation, concomitant with reduced SREBP2 expression. PCSK9 silencing also decreased endothelial CX3CL1 and CXCL16 expression and chemokine generation. In conclusion, PCSK9 inhibition impairs systemic inflammation and endothelial dysfunction by constraining leukocyte-endothelium interactions. PCSK9 blockade may constitute a new therapeutic approach to control the inflammatory state associated with FH, preventing further cardiovascular events in this cardiometabolic disorder.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Células Endoteliales , Hiperlipoproteinemia Tipo II , NADPH Oxidasa 5/metabolismo , Proproteína Convertasa 9/inmunología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacocinética , Línea Celular , Quimiocina CX3CL1/metabolismo , Quimiocina CXCL16/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/inmunología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Inhibidores de PCSK9/administración & dosificación , Inhibidores de PCSK9/farmacologíaRESUMEN
2-Prenylated benzopyrans represent a class of natural and synthetic compounds showing a wide range of significant activities. Polycerasoidol is a natural prenylated benzopyran isolated from the stem bark of Polyalthia cerasoides (Annonaceae) that exhibits dual PPARα/γ agonism and an anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium. Herein, we report the synthesis of three new series of prenylated benzopyrans containing one (series 1), two (series 2, "polycerasoidol" analogs) and three (series 3, "trans-δ-tocotrienolic acid" analogs) isoprenoid units in the hydrocarbon side chain at the 2-position of the chroman-6-ol (6-hydroxy-dihydrobenzopyran) scaffold. Isoprenoid moieties were introduced through a Grignard reaction sequence, followed by Johnson-Claisen rearrangement and subsequent Wittig olefination. hPPAR transactivation activity and the structure activity relationships (SAR) of eleven novel synthesized 2-prenylated benzopyrans were explored. PPAR transactivation activity demonstrated that the seven-carbon side chain analogs (series 1) displayed selectivity for hPPARα, while the nine-carbon side chain analogs (polycerasoidol analogs, series 2) did so for hPPARγ. The side chain elongation to 11 or 13 carbons (series 3) resulted in weak dual PPARα/γ activation. Therefore, 2-prenylated benzopyrans of seven- and nine-carbon side chain (polycerasoidol analogs) are good lead compounds for developing useful candidates to prevent cardiovascular diseases associated with metabolic disorders.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Benzopiranos/farmacología , PPAR alfa/agonistas , PPAR gamma/agonistas , Vitamina E/análogos & derivados , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Benzopiranos/síntesis química , Benzopiranos/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Vitamina E/síntesis química , Vitamina E/química , Vitamina E/farmacologíaRESUMEN
BACKGROUND: Higher education training in Medicine has considerably evolved in recent years. One of its main goals has been to ensure the training of students as future adequately qualified general practitioners (GPs). Tools need to be developed to evaluate and improve the teaching of Urology at the undergraduate level. Our objective is to identify the knowledge and skills needed in Urology for the real clinical practice of GPs. METHODS: An anonymous self-administered survey was carried out among GPs of Primary Care and Emergencies which sought to evaluate urological knowledge and necessary urological skills. The results of the survey were exported and descriptive statistics were performed using IBM SPSS Statistics version 19.0. RESULTS AND LIMITATIONS: A total of 127 answers were obtained, in which 'Urological infections', 'Renal colic', 'PSA levels and screening for prostate cancer', 'Benign prostatic hyperplasia', 'Hematuria', 'Scrotal pain', 'Prostate cancer diagnosis', 'Bladder cancer diagnosis', 'Urinary incontinence', and 'Erectile dysfunction' were rated as Very high or High formative requirements (>75%). Regarding urological skills, 'Abdominal examination', 'Interpretation of urinalysis', 'Digital rectal examination', 'Genital examination', and 'Transurethral catheterization' were assessed as needing Very high or High training in more than 80% of the surveys. The relevance of urological pathology in clinical practice was viewed as Very high or High in more than 80% of the responses. CONCLUSIONS: This study has shown helpful results to establish a differentiated prioritization of urological knowledge and skills in Primary Care and Emergencies. Efforts should be aimed at optimizing the teaching in Urology within the Degree of Medicine which consistently ensures patients' proper care by future GPs.
Asunto(s)
Médicos Generales , Urología , Competencia Clínica , Humanos , Masculino , Estudios Prospectivos , Estudiantes , Urología/educaciónRESUMEN
Leukocyte cell recruitment into the vascular subendothelium constitutes an early event in the atherogenic process. As the effect of the constitutive androstane receptor (CAR) on leukocyte recruitment and endothelial dysfunction is poorly understood, this study investigated whether the role of CAR activation can affect this response and the underlying mechanisms involved. Under physiological flow conditions, TNFα-induced endothelial adhesion of human leukocyte cells was concentration-dependently inhibited by preincubation of human umbilical arterial endothelial cells with the selective human CAR ligand CITCO. CAR agonism also prevented TNFα induced VCAM-1 expression, as well as MCP-1/CCL-2 and RANTES/CCL-5 release in endothelial cells. Suppression of CAR expression with a small interfering RNA abrogated the inhibitory effects of CITCO on these responses. Furthermore, CITCO increased interaction of CAR with Retinoid X Receptor (RXR) and reduced TNFα-induced p38-MAPK/NF-κB activation. In vivo, using intravital microscopy in the mouse cremasteric microcirculation treatment with the selective mouse CAR ligand TCPOBOP inhibited TNFα-induced leukocyte rolling flux, adhesion, and emigration and decreased VCAM-1 in endothelium. These results reveal that CAR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps in the leukocyte recruitment cascade. Therefore, CAR agonists may constitute a new therapeutic tool in controlling cardiovascular disease-associated inflammatory processes.