Search

Osteoarthritis, one of the most common joint degenerative pathologies, still has no cure, and current treatments, such as nonsteroidal anti-inflammatory drugs, can cause serious adverse effects when taken for a long time. Brown seaweed crude fucoidans are used for the clinical treatment of several pathologies. In this study, the therapeutical potential of these biocompounds was analyzed in primary chondrocytes and the 260TT human chondrocyte cell line. Crude fucoidan from Undaria pinnatifida (Up) and Sargassum muticum (Sm) was obtained by different extraction techniques (microwave-assisted extraction, pressurized hot-water extraction, ultrasound-assisted extraction) and chemically and structurally characterized by Fourier transform infrared spectroscopy, high-performance size-exclusion chromatography, proton nuclear magnetic resonance, and scanning electron microscopy. Once cell viability was confirmed in chondrocytes treated with crude fucoidans, we evaluated their anti-inflammatory effects, observing a significant reduction in IL-6 production stimulated by IL-1β. Findings were confirmed by analysis of IL-6 and IL-8 gene expression, although only fucoidans from Up achieved a statistically significant reduction. Besides this, the antioxidant capacity of crude fucoidans was observed through the upregulation of Nrf-2 levels and the expression of its transcriptional target genes HO-1 and SOD-2, with compounds from Up again showing a more consistent effect. However, no evidence was found that crude fucoidans modulate senescence, as they failed to reduced β-galactosidase activity, cell proliferation, or IL-6 production in chondrocytes stimulated with etoposide. Thus, the findings of this research seem to indicate that the tested crude fucoidans are capable of partially alleviating OA-associated inflammation and oxidative stress, but fail to attenuate chondrocyte senescence. Axencia Galega de Innovación-Xunta de Galicia | Ref. IN607A 2021/7 Xunta de Galicia | Ref. ED481D-2022-018 Ministerio de Ciencia, Innovación y Universidades | Ref. RYC2018-024454-I Xunta de Galicia | Ref. ED431F 2020/01

Review [Abstract] Control of excessive mitochondrial oxidative stress could provide new targets for both preventive and therapeutic interventions in the treatment of chronic inflammation or any pathology that develops under an inflammatory scenario, such as rheumatoid arthritis (RA). Increasing evidence has demonstrated the role of mitochondrial alterations in autoimmune diseases mainly due to the interplay between metabolism and innate immunity, but also in the modulation of inflammatory response of resident cells, such as synoviocytes. Thus, mitochondrial dysfunction derived from several danger signals could activate tricarboxylic acid (TCA) disruption, thereby favoring a vicious cycle of oxidative/mitochondrial stress. Mitochondrial dysfunction can act through modulating innate immunity via redox-sensitive inflammatory pathways or direct activation of the inflammasome. Besides, mitochondria also have a central role in regulating cell death, which is deeply altered in RA. Additionally, multiple evidence suggests that pathological processes in RA can be shaped by epigenetic mechanisms and that in turn, mitochondria are involved in epigenetic regulation. Finally, we will discuss about the involvement of some dietary components in the onset and progression of RA. Instituto de Salud Carlos III; PI17/00404 Instituto de Salud Carlos III; PI18/01803 Instituto de Salud Carlos III; PI19/01206 Instituto de Salud Carlos III; PI20/00793 Instituto de Salud Carlos III; PI21/01969 Instituto de Salud Carlos III; RICORS RD21/0002/0009 Xunta de Galicia; IN607A2017/11 Xunta de Galicia; IN607D2020/10

OBJECTIVE To evaluate the efficacy and safety of increasing the dose interval of subcutaneous tocilizumab (TCZ-SC) in patients with rheumatoid arthritis (RA) who are in clinical remission. METHODS RA patients with active disease and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or to a biologic agent were entered into a single-arm treatment phase with 162 mg of TCZ-SC administered once weekly (TCZ-SC 162 mg qw) as monotherapy or in combination with a csDMARD for 24 weeks. Patients who achieved clinical remission at weeks 20 and 24 were randomized to continue with the same regimen or to switch to 162 mg TCZ-SC administered every 2 weeks (TCZ-SC 162 mg q2w) for 24 weeks (open-label). Patients with a Disease Activity Score in 28 joints (DAS28) of

Cohorte de la Red de InvestigacioÂn en Sida (CoRIS)., [Objetives] Outcomes of people living with HIV (PLWH) developing non-AIDS events (NAEs) remain poorly defined. We aimed to classify NAEs according to severity, and to describe clinical outcomes and prognostic factors after NAE occurrence using data from CoRIS, a large Spanish HIV cohort from 2004 to 2013., [Design] Prospective multicenter cohort study., [Methods] Using a multistate approach we estimated 3 transition probabilities: from alive and NAE-free to alive and NAE-experienced (“NAE development”); from alive and NAE-experienced to death (“Death after NAE”); and from alive and NAE-free to death (“Death without NAE”). We analyzed the effect of different covariates, including demographic, immunologic and virologic data, on death or NAE development, based on estimates of hazard ratios (HR). We focused on the transition “Death after NAE”., [Results] 8,789 PLWH were followed-up until death, cohort censoring or loss to follow-up. 792 first incident NAEs occurred in 9.01% PLWH (incidence rate 28.76; 95% confidence interval [CI], 26.80–30.84, per 1000 patient-years). 112 (14.14%) NAE-experienced PLWH and 240 (2.73%) NAE-free PLWH died. Adjusted HR for the transition “Death after NAE” was 12.1 (95%CI, 4.90–29.89). There was a graded increase in the adjusted HRs for mortality according to NAE severity category: HR (95%CI), 4.02 (2.45–6.57) for intermediate-severity; and 9.85 (5.45–17.81) for serious NAEs compared to low-severity NAEs. Male sex (HR 2.04; 95% CI, 1.11–3.84), age>50 years (1.78, 1.08–2.94), hepatitis C-coinfection (2.52, 1.38–4.61), lower CD4 cell count at cohort entry (HR 2.49; 95%CI 1.20–5.14 for CD4 cell count below 200 and HR 2.16; 95%CI 1.01–4.66 for CD4 cell count between 200–350, both compared to CD4 cell count higher than 500) and concomitant CD4, [Conclusion] NAEs, including low-severity events, increase prominently the risk for mortality in PLWH. Prognostic factors differ between NAE-experienced and NAE-free persons. These findings should be taken into account in the clinical management of PLWH developing NAEs and may permit more targeted prevention efforts., This work was supported by the RD12/0017/0023 and RD 16/0025/0038 projects as part of the Plan Nacional R + D + I and cofinanced by ISCIII- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER), FIS (PI08/893), FIS (PI13/02256), FIS (PI16/01740), FISABIO UGP-14-197, Contrato de Intensificación de la Actividad Investigadora INT 14/00207, Contrato Predoctotal FISABIO 2015 (UGP-15-152) and Contrato Río Hortega (CM15/00187).

Background The relationship between host microRNAs (miRNA), viral control and immune response has not yet been elucidated in the field of HIV. The aim of this study was to assess the differential miRNA profile in CD8+ T-cells between HIV-infected individuals who differ in terms of viral replication control and immune response. Methods miRNA profile from resting and CD3/CD28-stimulated CD8+ T-cells from uninfected individuals (HIV-, n = 11), Elite Controllers (EC, n = 15), Viremic Controllers (VC, n = 15), Viremic Progressors (VP, n = 13) and HIV-infected patients on therapy (ART, n = 14) was assessed using Affymetrix miRNA 3.1 arrays. After background correction, quantile normalization and median polish summarization, normalized data were fit to a linear model. The analysis comprised: resting samples between groups; stimulated samples between groups; and stimulated versus resting samples within each group. Enrichment analyses of the putative target genes were perfomed using bioinformatic algorithms. Results A downregulated miRNA pattern was observed when resting samples from all infected groups were compared to HIV-. A miRNA downregulation was also observed when stimulated samples from EC, ART and HIV- groups were compared to VP, being hsa-miR-4492 the most downregulated. Although a preferential miRNA downregulation was observed when stimulated samples were compared to the respective resting samples, VP presented a differential miRNA expression pattern. In fact, hsa-miR-155 and hsa-miR-181a were downregulated in VP whereas in the other groups, either an upregulation or no differences were observed after stimulation, respectively. Overall, functional enrichment analysis revealed that the predicted target genes were involved in signal transduction pathways, metabolic regulation, apoptosis, and immune response. Conclusions Resting CD8+ T-cells do not exhibit a differential miRNA expression between HIV-infected individuals but they do differ from non-infected individuals. Moreover, a specific miRNA pattern is present in stimulated CD8+ T-cells from VP which could reflect a detrimental pattern in terms of CD8+ T-cell immune response.

Background: Immune-mediated inflammatory diseases (IMIDs) are a group of complex and prevalent diseases where disease diagnostic and activity monitoring is highly challenging. The determination of the metabolite profiles of biological samples is becoming a powerful approach to identify new biomarkers of clinical utility. In order to identify new metabolite biomarkers of diagnosis and disease activity, we have performed the first large-scale profiling of the urine metabolome of the six most prevalent IMIDs: rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. Methods: Using nuclear magnetic resonance, we analyzed the urine metabolome in a discovery cohort of 1210 patients and 100 controls. Within each IMID, two patient subgroups were recruited representing extreme disease activity (very high vs. very low). Metabolite association analysis with disease diagnosis and disease activity was performed using multivariate linear regression in order to control for the effects of clinical, epidemiological, or technical variability. After multiple test correction, the most significant metabolite biomarkers were validated in an independent cohort of 1200 patients and 200 controls. Results: In the discovery cohort, we identified 28 significant associations between urine metabolite levels and disease diagnosis and three significant metabolite associations with disease activity (P-FDR < 0.05). Using the validation cohort, we validated 26 of the diagnostic associations and all three metabolite associations with disease activity (PFDR < 0.05). Combining all diagnostic biomarkers using multivariate classifiers we obtained a good disease prediction accuracy in all IMIDs and particularly high in inflammatory bowel diseases. Several of the associated metabolites were found to be commonly altered in multiple IMIDs, some of which can be considered as hub biomarkers. The analysis of the metabolic reactions connecting the IMID-associated metabolites showed an overrepresentation of citric acid cycle, phenylalanine, and glycine-serine metabolism pathways. Conclusions: This study shows that urine is a source of biomarkers of clinical utility in IMIDs. We have found that IMIDs show similar metabolic changes, particularly between clinically similar diseases and we have found, for the first time, the presence of hub metabolites. These findings represent an important step in the development of more efficient and less invasive diagnostic and disease monitoring methods in IMIDs.

OBJECTIVES: We aim to describe rates and risk factors of Hepatitis C Virus (HCV) diagnoses, follow-up HCV testing and HCV seroconversion from 2004-2011 in a cohort of HIV-positive persons in Spain. METHODS: CoRIS is a multicentre, open and prospective cohort recruiting adult HIV-positive patients naïve to antiretroviral therapy. We analysed patients with at least one negative and one follow-up HCV serology. Incidence Rates (IR) were calculated and multivariate Poisson regression was used to estimate adjusted Rates Ratios (aIRR). RESULTS: Of 2112 subjects, 53 HCV diagnoses were observed, IR = 0.93/100 py (95%CI: 0.7-1.2). IR increased from 0.88 in 2004-05 to 1.36 in 2010-11 (aIRR = 1.55; 95%CI: 0.37-6.55). In men who have sex with men (MSM) from 0.76 to 1.10 (aIRR = 1.45; 95%CI: 0.31-6.82); in heterosexual (HTX) subjects from 1.19 to 1.28 (aIRR = 1.08; 95%CI: 0.11-10.24). HCV seroconversion rates decreased from 1.77 to 0.65 (aIRR = 0.37; 95%CI: 0.12-1.11); in MSM from 1.06 to 0.49 (aIRR = 0.46; 95%CI: 0.09-2.31); in HTX from 2.55 to 0.59 (aIRR = 0.23; 95%CI: 0.06-0.98). HCV infection risk was higher for injecting drug users (IDU) compared to HTX (aIRR = 9.63;95%CI: 2.9-32.2); among MSM, for subjects aged 40-50 compared to 30 or less (IRR = 3.21; 95%CI: 1.7-6.2); and among HTX, for female sex (aIRR = 2.35; 95%CI: 1.03-5.34) and

To describe tuberculosis (TB) incidence, risk factors, clinical presentation, disease management and outcomes in human immunodeficiency virus (HIV) infected patients from the CoRIS cohort, Spain, 2004-2010.Open multicentre cohort of antiretroviral treatment (ART) naïve patients at entry. Incidence and risk factors were evaluated using multivariate Poisson regression.Among 6811 patients, 271 were eligible for the study and 198 for the estimation of the incidence rate; TB incidence ranged from 12.1 to 14.1/1000 person-years. TB was associated with low education level (rate ratio [RR] 2.65, 95%CI 1.73-4.07), being sub-Saharan African (RR 3.14, 95%CI 1.81-5.45), heterosexual (RR 2.01, 95%CI 1.22-3.29) or an injecting drug user (RR 2.11, 95%CI 1.20-3.69), not undergoing ART (RR 3.33, 95%CI 2.22-4.76), CD4200 cells/mm(3) (RR 5.20, 95%CI 3.25-8.33) and log-viral load of 4-5 (RR 5.44, 95%CI 3.28-9.02) or5 (RR 13.10, 95%CI 8.27-20.76). Overall, 87% were new cases and 13% were previously treated cases; 175 (65%) were bacteriologically confirmed. Drug susceptibility testing was performed in 146 (83%) patients: resistance to first-line drugs was 11.1% in new and 36.4% in previously treated cases. Standard anti-tuberculosis treatment with four or three drugs was prescribed in respectively 55% and 36% of cases. Treatment default was 11%, and was higher among previously treated cases; 80% received ART during anti-tuberculosis treatment, 80% of new and 50% of previously treated cases were cured or completed treatment, and 18 (6.6%) died.TB incidence in HIV-infected patients remains high. Interventions should include early HIV diagnosis and access to ART, enhanced bacteriological confirmation, wider use of four-drug regimens and reduction in treatment default.

Objective.We evaluated whether a single-nucleotide polymorphism (SNP) of theTRAF6gene previously associated with systemic lupus erythematosus and rheumatoid arthritis may be a common risk factor for systemic sclerosis (SSc) and giant cell arteritis (GCA).Methods.A total of 1185 patients with SSc, 479 patients with biopsy-proven GCA, and 1442 unrelated healthy controls of white Spanish origin were genotyped for the rs540386 variant using a specifically designed TaqMan©allele discrimination assay.Results.No significant associations of this SNP with global SSc or GCA were found. This was also the case when the potential associations of theTRAF6polymorphism with the main clinical phenotypes of the 2 diseases (e.g., limited cutaneous and diffuse cutaneous SSc, or presence of polymyalgia rheumatica and visual ischemic manifestations in GCA) were assessed.Conclusion.Our data do not support a role of the rs540386TRAF6variant as a key component of the genetic network underlying SSc and GCA.

To appraise the incidence of liver toxicity in a population of patients receiving fosamprenavir/ritonavir (FPV/r) with a high frequency of viral hepatitis co-infection.636 patients, 341 (54%) with HCV antibodies and 38 (5.6%) bearing serum HBsAg, were recruited. All of them received FPV/r 700/100 twice every day. 93 (27%) patients who tested positive for HCV antibodies showed an AST to platelet ratio index (APRI) higher than 1.5, consistent with significant liver fibrosis.After a median (range) follow-up time of 6.91 (0.46-20.66) months, 3 (0.47%) patients developed grade 3 ALT elevation. All the former patients were hepatitis virus co-infected, 2 with hepatitis C virus and 1 with hepatitis B virus. The frequency of grade 3 ALT elevation in patients with HCV antibodies was 0.58% and in those harbouring HBsAg it was 2.63%. 4 (0.62%) patients suffered from a liver decompensation and 1 died due to a hepatic cause while on follow-up. No patients with APRI equal to or higher than 1.5 showed grade 3 ALT elevation.The incidence of adverse hepatic events in patients receiving FPV/r including combinations seems to be low, even in subjects co-infected with hepatitis virus and in those with significant liver fibrosis.

To analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004-2013). Cox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 4 years, aHRLP.vs.nLP = 1.5(0.7-3.1). First-year's main cause of death was HIV/AIDS (73%); and malignancies among those surviving >4 years (32%). HIV/AIDS-related deaths were more likely in LP (59.2% vs. 25.0%; p 50.vs.

To study the effect of steroidal and nonsteroidal antiinflammatory drugs (NSAID) on cyclooxygenase (COX-1 and COX-2) activity in human articular chondrocytes.Chondrocytes were isolated from articular cartilage of donors with no articular disease. Unstimulated and interleukin 1 (IL-1) stimulated chondrocytes were used as models to study the effects of drugs on COX-1 and COX-2. Cells were incubated with vehicle or drugs; supernatants were removed and the level of prostaglandin E2 (PGE2) in each sample was determined by enzyme immunoassay. IC50 were calculated from the reduction in PGE2 content by different concentrations of the test substance by linear regression analysis.COX- mRNA was detected in unstimulated cells, but stimulation with IL-1 for up 12 h did not modify the levels of COX-1 mRNA. In contrast, COX-2 mRNA was not detectable in unstimulated cells, but it was induced by IL-1. Dexamethasone inhibited COX-2 mRNA expression induced by IL-1. COX-2 protein levels correlated with mRNA expression. Dexamethasone was the strongest drug inhibitor of COX-2 (IC50 = 0.0073 microM). However, it did not inhibit COX-1 activity. Among all NSAID tested, meloxicam and aspirin were the least potent inhibitors of COX-1 (IC50 = 36.6 microM and 3.57 microM, respectively). Indomethacin and diclofenac were the most potent inhibitors of COX-1 (IC50 = 0.063 microM and 0.611 microM, respectively) and COX-2 isoforms (IC50 = 0.48 microM and IC50 = 0.63 microM, respectively). Meloxicam was a more potent inhibitor of COX-2 (IC50 = 4.7 microM) than aspirin (IC50 = 29.3 microM) and similar to piroxicam (IC50 = 4.4 microM). Among all drugs tested dexamethasone showed the greatest selectivity for COX-2 and meloxicam was the NSAID with the best COX-2/COX-1 ratio (r = 0.12). Aspirin and piroxicam were about 8 times more active against COX-1 than COX-2, indomethacin was 7 times more active, and diclofenac was an equipotent inhibitor of COX-1 and COX-2.We found that COX-1 and COX-2 isoforms are expressed in human chondrocytes at rest and in IL-1 stimulated cells, respectively. Antiinflammatory drugs have different capacities to inhibit COX enzyme in human articular chondrocytes.

Prevalence of transmitted drug resistance (pTDR) to antiretroviral drugs in Spain (2007–2012) was estimated using the CoRIS cohort, adjusting its territorial distribution and transmission route to the reference population from the Spanish Information System on New human immunodeficiency virus diagnoses. A total of 2702 patients from ten autonomous communities and with naive FASTA sequence within 6 months of human immunodeficiency virus diagnosis were selected. Weighted pTDR, estimated using the inverse probability of selection in the sample by autonomous communities and transmission group, was 8.12% (95% CI 6.44–9.80), not significantly different from unweighted pTDR. We illustrate how proportional weighting can maximize representativeness of cohort-based data, and its value to monitor pTDR at country level.