PCSK9 induces a pro-inflammatory response in macrophages

Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250\u2009\uf7\u20092.5\u2009\ub5g/ml) of human recombinant PCSK9 (hPCSK9). After 24\u2009h incubation with 2.5\u2009\ub5g/ml PCSK9, a significant induction of IL-1\u3b2, IL-6, TNF-\u3b1, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-\u3b1 (2.4\u2009\ub1\u20090.5 fold) and IL-1\u3b2 (8.6\u2009\ub1\u20091.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-\u3b1 mRNA in murine LDLR-/- bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3\u2009\ub1\u20091.6 fold vs 31.1\u2009\ub1\u20096.1 fold for LDLR-/- and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-\u3b1 plasma levels of healthy adult subjects (males 533, females 537) was observed (B\u2009=\u20098.73, 95%CI 7.54\u2009\uf7\u20099.93, p\u2009<\u20090.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR

Association of Microvesicles With Graft Patency in Patients Undergoing CABG Surgery

Abstract Background Graft patency is one of the major determinants of long-term outcome following coronary artery bypass graft surgery (CABG). Biomarkers, if indicative of the underlying pathophysiological mechanisms, would suggest strategies to limit graft failure. The prognostic value of microvesicles (MVs) for midterm graft patency has never been tested. Objectives The aim of this study was to evaluate whether MV pre-operative signature (number, cellular origin, procoagulant phenotype) could predict midterm graft failure and to investigate potential functional role of MVs in graft occlusion. Methods This was a nested case-control substudy of the CAGE (CoronAry bypass grafting: factors related to late events and Graft patency) study that enrolled 330 patients undergoing elective CABG. Of these, 179 underwent coronary computed tomography angiography 18 months post-surgery showing 24% graft occlusion. Flow cytometry MV analysis was performed in 60 patients (30 per group with occluded [cases] and patent [control subjects] grafts) on plasma samples collected the day before surgery and at follow-up. Results Before surgery, cases had 2- and 4-fold more activated platelet-derived and tissue-factor positive MVs respectively than control subjects. The MV procoagulant capacity was also significantly greater. Altogether this MV signature properly classified graft occlusion (area under the curve 0.897 [95% confidence interval: 0.81 to 0.98]; p Conclusions The pre-operative signature of MVs is independently associated with midterm graft occlusion in CABG patients and a cumulative MV score stratifies patients' risk. Because the MV signature mirrors platelet activation, patients with a high MV score could benefit from a personalized antiplatelet therapy

BK virus salivary shedding and viremia in renal transplant recipients

Objectives: This study aimed to verify the presence of polyomavirus BK (BKPyV) in the saliva of kidney transplant recipients and to correlate it with blood viremia. Material and Methods: We have conducted a crosssectional study with a sample involving 126 renal transplant recipients. 126 samples of saliva and 52 samples of blood were collected from these patients. Detection and quantification of BKPyV were performed using a real-time PCR. To compare the presence of BKPyV in blood and saliva, the binomial proportion test was used. To verify associations between salivary shedding BKPyV and post-transplant periods (in months), the Mann-Whitney test was used. Spearman’s correlation was used to correlate the viral load in the saliva with blood of kidney transplant recipients. Results: The mean age of the study group was 51.11±12.45 years old, and 69 participants (54.8%) were female, with a mean post-transplantation time of 4.80±6.04 months. BKPyV was quantified in several samples of saliva and blood, with medians of 1,108 cp/mL and 1,255 cp/mL, respectively. Only 16/52 (30.8%) participants presented BKPyV in blood, and 59/126 (46.8%) excreted the virus in saliva (p=0.004). BKPyV shedding was found in patients at a shorter post-transplantation period (3.86±5.25, p=0.100). A weak correlation was observed between viral quantification in saliva and blood (Spearman’s correlation coefficient=0.193). Conclusion: The results of this study suggested that, although saliva excretes more BKPyV than blood, there is no reliable correlation between salivary shedding and blood viremia, showing two independent compartments of viral replication

Overcoming limitations of current antiplatelet drugs: A concerted effort for more profitable strategies of intervention

Platelets play a central role in the pathophysiology of atherothrombosis, an inappropriate platelet activation leading to acute ischemic complications (acute myocardial infarction, ischemic stroke). In view of this, platelets are a major target for pharmacotherapy. Presently, the main classes of antiplatelet agents approved for the use in such complications are aspirin and fhienopyridines. Although antiplatelet treatment with these two types of drugs, alone or in combination, leads to a significant reduction of non-fatal myocardial infarction (−32%), non-fatal stroke (−25%), and of cardiovascular death (−17%), a residual risk persists

Active monitoring of tuberculosis cases during the Covid-19 pandemic in a general hospital for acute patients in Buenos Aires City

A pesar de la existencia de un tratamiento efectivo, la persistencia de la tuberculosis (TB) en la Ciudad de Buenos Aires (CABA) señala los obstáculos presentes en la accesibilidad a los servicios de salud y la necesidad de visibilizar los determinantes sociales en la adherencia a los tratamientos antituberculosos. El contexto de la pandemia de covid-19 y del aislamiento social preventivo y obligatorio (ASPO) implicaron un fuerte desafío para reorganizar los servicios de salud y afecta de manera exacerbada a los grupos en situación de pobreza y vulnerabilidad social. Este artículo se propone señalar los principales resultados de la implementación de una modalidad de seguimiento activo de los casos de tuberculosis en un hospital general de agudos de CABA entre 2020 y 2021. Se utilizó un diseño de investigación en implementación con una metodología cuantitativa y cualitativa para reconocer los principales obstáculos en el seguimiento y la adherencia a los tratamientos antifímicos en el contexto de la pandemia de covid-19. Se identificaron los grupos sociales afectados por la TB con mayor vulnerabilidad social para el seguimiento: población en situación de calle, con consumo problemático de sustancias y población transfemenina. Se señala el armado de redes comunitarias con referentes de organizaciones de la sociedad civil como una estrategia efectiva para acompañar a esta población.Despite an effective treatment, the persistence of tuberculosis (TB) in the City of Buenos Aires (CABA, its acronym in Spanish) indicates the obstacles in accessibility to health services and the need to make the social determinants of adherence to the tuberculosis treatments visible. The covid-19 pandemic together with the preventive and compulsory social isolation (ASPO, its acronym in Spanish) mean a strong challenge for reorganizating health services and exacerbate the problems of poor and socially vulnerable groups. This article aims to show the main results of implementing an active follow-up modality of TB cases in a general hospital for acute patients in CABA in 2020-2021. The main obstacles in the follow-up and adherence to anti-fimic treatments in the context of the covid-19 pandemic were identified through a research design with quantitative and qualitative methodology. Social groups affected by TB and higher social vulnerability were identified for the follow-up: homeless, those with problematic substance use, and trans-female. Setting community networks with mentors from civil society organizations were an effective strategy for accompanying these populations.Fil: Pereyra, Andrés Martín. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Barrios, Rocio. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Aranda, Jimena. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Herrero, María Belén. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Longordo, Marina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Hering, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Ben, Graciela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Koufios, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Marcuzz, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Camera, Eugenia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Catalano, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Paz, Enroque. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; Argentin

Use and Prescription of Direct Oral Anticoagulants in Older and Frail Patients with Atrial Fibrillation: A Multidisciplinary Consensus Document

In the last twelve years the clinical management of patients with atrial fibrillation has been revolutionised by the introduction of direct oral anticoagulants. Despite the large amount of evidence produced, some populations remain relatively poorly explored regarding the effectiveness and safety of direct oral anticoagulants, such as the oldest and/or frailest individuals. Frailty is clinical syndrome characterized by a reduction of functions and physiological reserves which results in individuals having higher vulnerability. While current evidence underlines a relationship between atrial fibrillation and frailty, particularly in determining a higher risk of adverse outcomes, data regarding effectiveness and safety of direct oral anticoagulants in frailty atrial fibrillation patients are still lacking, leaving uncertainty about how to guide prescription in this specific subgroup. On these premises, this multidisciplinary consensus document explains why it would be useful to integrate the clinical evaluation performed through comprehensive geriatric assessment to gather further elements to guide prescription of direct oral anticoagulants in such a high-risk group of patients

An Intense and Short-Lasting Burst of Neutrophil Activation Differentiates Early Acute Myocardial Infarction from Systemic Inflammatory Syndromes

BACKGROUND: Neutrophils are involved in thrombus formation. We investigated whether specific features of neutrophil activation characterize patients with acute coronary syndromes (ACS) compared to stable angina and to systemic inflammatory diseases. METHODS AND FINDINGS: The myeloperoxidase (MPO) content of circulating neutrophils was determined by flow cytometry in 330 subjects: 69 consecutive patients with acute coronary syndromes (ACS), 69 with chronic stable angina (CSA), 50 with inflammation due to either non-infectious (acute bone fracture), infectious (sepsis) or autoimmune diseases (small and large vessel systemic vasculitis, rheumatoid arthritis). Four patients have also been studied before and after sterile acute injury of the myocardium (septal alcoholization). One hundred thirty-eight healthy donors were studied in parallel. Neutrophils with normal MPO content were 96% in controls, >92% in patients undergoing septal alcoholization, 91% in CSA patients, but only 35 and 30% in unstable angina and AMI (STEMI and NSTEMI) patients, compared to 80%, 75% and 2% of patients with giant cell arteritis, acute bone fracture and severe sepsis. In addition, in 32/33 STEMI and 9/21 NSTEMI patients respectively, 20% and 12% of neutrophils had complete MPO depletion during the first 4 hours after the onset of symptoms, a feature not observed in any other group of patients. MPO depletion was associated with platelet activation, indicated by P-selectin expression, activation and transactivation of leukocyte β2-integrins and formation of platelet neutrophil and -monocyte aggregates. The injection of activated platelets in mice produced transient, P-selectin dependent, complete MPO depletion in about 50% of neutrophils. CONCLUSIONS: ACS are characterized by intense neutrophil activation, like other systemic inflammatory syndromes. In the very early phase of acute myocardial infarction only a subpopulation of neutrophils is massively activated, possibly via platelet-P selectin interactions. This paroxysmal activation could contribute to occlusive thrombosis

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension