Disfunción metabólica en la progresión de la artrosis

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 21-04-2017La artrosis, es una patología multifactorial, extremadamente común, que afecta a las articulaciones diartrodiales provocando dolor e incapacidad funcional, y para la que no existe ningún tratamiento. La recomendación más extendida para mejorar el pronóstico, es la modificación del estilo de vida para evitar factores de riesgo asociados a desordenes metabólicos como la diabetes y el síndrome metabólico. Un mayor conocimiento de los mecanismos celulares responsables de dichas asociaciones, sería fundamental para una mejor caracterización de la patogenia de la artrosis, facilitando así, nuevos abordajes terapéuticos. Con el objetivo de profundizar en los mecanismos por los que la hiperglucemia y la hiperlipemia podrían modular la evolución de la artrosis, hemos desarrollado dos aproximaciones. Por un lado, pusimos a punto un sistema de cultivo en tres dimensiones de condrocitos primarios, artrósicos para estimularlos con altas concentraciones de glucosa. También, realizamos un estudio en pacientes artrósicos con alteraciones en el metabolismo de la glucosa. Como resultado, hemos demostrado que una concentración elevada de glucosa induce un fenotipo hipertrófico en condrocitos artrósicos en cultivo, proceso que se inhibe cuando se impide la O-β-N-Acetilglicosilación proteica. Observamos además, que los pacientes artrósicos con diabetes muestran un aumento en la expresión de marcadores de hipertrofia en el cartílago, superior al que observamos en los pacientes con artrosis sin alteraciones metabólicas. Por otro lado, hemos trabajado con un modelo de artrosis en conejos con hiperlipemia para evaluar el efecto de la combinación de estos factores en los tejidos articulares, especialmente en la membrana adiposa infrapatelar. La hiperlipemia agravó el daño histológico en la membrana sinovial de los conejos artrósicos produciéndose una invasión de macrófagos, tejido fibrótico, incrementó la destrucción del tejido adiposo, reducción en el tamaño y el número de los adipocitos y reducción de los niveles de adipoquinas en la sinovial. Este trabajo describe alguno de los mecanismos por los que la hiperlipemia y la hiperglucemia podrían agravar el desarrollo de la artrosis humana. Así, nuestros resultados apoyan la idea de la existencia de un fenotipo metabólico de artrosis. Asimismo, estos datos podrían abrir nuevas líneas de investigación sobre la O-β-N-Acetilglicosilación de proteínas, y su posible modificación en el tratamiento de la artrosis o sobre la identificación de nuevas dianas en los distintos tejidos articulares, más allá del cartílago en pacientes con características distintivas como la dislipemia.Osteoarthritis (OA) is an extremely common multifactorial disease that affects diartrodial articulations, causing pain and functional loss. There is not any available pharmacological treatment, and the most extended recommendation is to follow a healthy lifestyle in order to avoid metabolic disorder related risk factors, as obesity, diabetes or metabolic syndrome. A greater knowledge of the cellular mechanisms behind this association is essential for a better characterization of the pathogenesis of osteoarthritis, thus, facilitating new therapeutic approaches. With the objective of deepening on the mechanisms by hyperglycemia and hyperlipemia, modulate the evolution of OA, we have developed two different approaches. First, we have worked with a three-dimensional primary osteoarthritic chondrocyte culture system to study the influence of high glucose concentrationse. We also performed a study in patients with impaired glucose metabolism. As a result, we have shown that a high concentration of glucose induces a hypertrophic phenotype in cultured chondrocytes. Also, that this process is inhibited when protein O-β-N-Acetylglycosylation is impaired. Similarly, compared to osteoarthritic patients without identified metabolic alterations, patients with osteoarthritis and diabetes show an increase of hypertrophyc marker expression in the cartilage. Second, we developed an osteoarthritic, hypercholesterolemic rabbit model to evaluate the effect of the combination of these factors on the articular tissues, especially in the infrapatellar adipose membrane. Hyperlipemia aggravated histological damage of the synovial membrane of this rabbits leading to macrophage invasion, fibrotic tissue, increased destruction of adipose tissue with reduced adipocyte size and a decrease of synovial adipokines. This paper describes some of the mechanisms by which hyperlipemia and hyperglycemia aggravate the development of human OA. Therefore, our results support the idea of the existence of a metabolic phenotype of osteoarthritis. In addition, these data opens a field to research on protein O-β-N-Acetylglycosylation, and its possible modification in the osteoarthritis treatment or in the identification of new pharmacologic targets in the different articular tissues, beyond the cartilage

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Increased synovial lipodystrophy induced by high fat diet aggravates synovitis in experimental osteoarthritis

Abstract Background Metabolic syndrome (MetS) may be associated with knee osteoarthritis (OA), but the association between the individual components and OA are not well-understood. We aimed to study the effect of hypercholesterolemia on synovial inflammation in knee OA. Methods OA was surgically induced in rabbits fed with standard diet (OA group, n = 10) or in rabbits fed with high fat diet (OA-HFD, n = 10). Healthy rabbits receiving standard diet (Control, n = 10) or fed with HFD (HFD, n = 6) were also monitored. Twelve weeks after OA induction, synovial membranes were isolated and processed for studies. Results Animals fed HFD showed higher levels of total serum cholesterol, triglycerides and C-reactive protein than control rabbits. Twelve weeks after OA induction, synovial membrane inflammation and macrophage infiltration were increased in rabbits with OA, particularly in the OA-HFD group. Extensive decrease of synovial adipose tissue area, adipocyte size and perilipin-1A synthesis were observed in the OA-HFD group in comparison to the OA and control groups. The HFD further increased the proinflammatory mediators IL-1β, IL-6 and TNF in the OA synovium. However, the synovial gene expression of adipokines, such as leptin and adiponectin, were markedly decreased in the rabbits with OA, especially in the OA-HFD group, in correlation with adipose tissue loss. However, circulating leptin was upregulated in the HFD and OA-HFD groups. Conclusion Our results indicate that a HFD is an aggravating factor worsening synovial membrane inflammation during OA, guided by increased infiltration of macrophages and removal of the adipose tissue, together with a remarkable presence of proinflammatory factors. Synovial adipocytes and dyslipemia could probably play pivotal roles in OA joint deterioration in patients with MetS, supporting that the link between obesity and OA transcends mechanical loading

Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set

Background: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients.Methods: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method.Results: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO.Conclusions: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids

Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave : the global UNITE-COVID study

Purpose To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%-50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality