PCSK9 regulates Nox2-mediated platelet activation via CD36 receptor in patients with atrial fibrillation

Background: High levels of proprotein convertase subtilisin/kexin 9 (PCSK9) is predictive of cardiovascular events (CVEs) in atrial fibrillation (AF). We hypothesized that PCSK9 may directly induce platelet activation (PA). Methods: We measured platelet aggregation, recruitment, Thromboxane B2 (TxB2) formation and soluble P-selectin levels as markers of PA and soluble Nox2-derived peptide (sNox2-dp), H2O2, isoprostanes and oxidized Low-Density-Lipoprotein (oxLDL) to analyze oxidative stress (OS) in 88 patients having PCSK9 values < (n = 44) or > (n = 44) 1.2 ng/mL, balanced for age, sex and cardiovascular risk factors. Furthermore, we investigated if normal (n = 5) platelets incubated with PCSK9 (1.0–2.0 ng/mL) alone or with LDL (50 µg/mL) displayed changes of PA, OS and down-stream signaling. Results: PA and OS markers were significantly higher in patients with PCSK9 levels > 1.2 ng/mL compared to those with values < 1.2 ng/mL (p < 0.001). Levels of PCSK9 significantly correlated with markers of PA and OS. Platelets incubation with PCSK9 increased PA, OS and p38, p47 and Phospholipase A2 (PLA2) phosphorylation. These changes were amplified by adding LDL and blunted by CD36 or Nox2 inhibitors. Co-immunoprecipitation analysis revealed an immune complex of PCSK9 with CD36. Conclusions: We provide the first evidence that PCSK9, at concentration found in the circulation of AF patients, directly interacts with platelets via CD36 receptor and activating Nox2: this effect is amplified in presence of LDL

Are interferon-gamma release assays reliable to detect tuberculosis infection in patients with rheumatoid arthritis treated with Janus kinase inhibitors

Screening for latent tuberculosis infection is recommended in patients with rheumatoid arthritis (RA) starting Janus kinase inhibitors (Jaki). Interferon (IFN)-gamma release assays (IGRAs) are increasingly used for this purpose. Jaki tend to decrease the levels of IFNs, questioning the reliability of IGRAs during treatment with these drugs. Objectives: To compare the performance of QuantiFERON-TB Gold Plus (QFT-P) and QFT Gold In-tube (QFT-GIT) in RA patients treated with Jaki. Methods: RA patients underwent QFT-P and QFT-GIT at baseline (T0), and after 3 (T3) and 12 months (T12) of treatment with Jaki. The agreement between the two tests was calculated. The agreement between IGRAs and tuberculin skin test (TST) or chest radiography at baseline was also determined. The variability of QTF-P results was longitudinally assessed. Results: Twenty-nine RA patients (F/M 23/6; median age/IQR 63/15.5 years; median disease duration/IQR 174/216 months) were enrolled. A perfect agreement was found between QFT-P and QFT-GIT at all times (κ = 1). At T0, no agreement was recorded between IGRAs and TST (κ = -0.08) and between TST and chest radiography (κ = -0.07), a low agreement was found between QFT-P and chest radiography (κ = 0.17). A variation of 33.3% in the results of QFT-P was recorded at T3 vs T0, of 29.4% at T12 vs T0, and of 11.8% at T12 vs T3. The median levels of IFN-γ produced by lymphocytes in response to the mitogen of QFT-P decreased after 3 months followed by an increase after 12 months (not significant). No change in the median number of circulating lymphocytes was documented. Glucocorticoids intake was associated with a higher probability of negative or indeterminate IGRA results at T0 (p<0.0001). Conclusion: A response to IGRAs is detectable during treatment with Jaki. However, fluctuations in the results of IGRAs have been observed in the absence of correlation with clinical outcomes, thus challenging their interpretation

An observational study on chronic pain biomarkers in fibromyalgia and osteoarthritis patients:.which role for mu opioid receptor’s expression on NK cells.

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. Here, we investigate the role of MLM on natural killer (NK) cells in the same patients. Twenty-nine FM and twelve OA patients were analyzed, and twenty-three pain-free subjects were considered as the control group. Blood samples were collected to perform immunophenotyping and Western blot analysis. Biological and clinical data were statistically analyzed. The final results showed that the percentage of NK cells expressing Mu was statistically lower in FM and OA patients than in pain-free subjects, as already demonstrated for B cells. A Western blot analysis was performed in order to detect NK cells' functional status. Moreover, the correlation analysis of MLM expression with pharmacological therapy did not show any significant results. In conclusion, here, we confirm the role of MLM as a suitable marker for chronic pain and underline NK cells as a new possible immune cell type involved in the "Mu opioid receptor reserve theory"

Transcatheter aortic valve implantation results are not superimposable to surgery in patients with aortic stenosis at low surgical risk

Background: The aim of this meta-analysis was to compare the impact of transcatheter aortic valve implantation (TAVI) vs. surgical aortic valve replacement (SAVR) in patients with severe aortic valve stenosis at low surgical risk. Methods: All randomized controlled trials (RCTs) and observational studies (Obs) published from January 2014 until March 31st, 2020 were retrieved through the PubMed computerized database and at the site https://www.clinicaltrials.com. The relative risk (RR) with the 95% confidence interval (CI) was used to evaluate the effect of the intervention under comparison. The primary endpoints were all-cause 30-day mortality and 1-year mortality. The 30-day safety endpoints were: stroke, acute kidney injury stage 2 or 3, major bleeding, moderate/severe paravalvular leak, need for new permanent pacemaker (PM) implantation. Results: After detailed review 9 studies, related to 4 RCTs and 5 Obs, were selected. The overall analysis of RCTs plus Obs showed a significantly lower 30-day mortality for TAVI (RR = 0.55; 95% CI 0.45–0.68, p < 0.00001; I2 = 0%). However, an increased risk of new PM implantation (RR = 2.87; 95% CI 2.01–3.67, p < 0.00001, I2 = 0%) and of paravalvular leak (RR = 7.28; 95% CI 3.83–13.81, p < 0.00001, I2 = 0%) was observed in TAVI compared to SAVR. On the contrary, a lower incidence of major bleeding (RR = 0.38; 95% CI 0.27–0.54, p < 0.00001, I2 = 0%) and of acute kidney injury was observed (RR = 0.33; 95% CI 0.19–0.56, p < 0.0001, I2 = 0%) in TAVI. Conclusions: TAVI and SVAR in the treatment of AS in the patients at low surgical risk are not superimposable. In particular, if 30-day and 1-year mortality, major bleeding and acute kidney injury were significantly lower for TAVI, the need of new PM implantation and paravalvular leak were significantly lower in SAVR. Consequently, we suggest the need of more trials to evaluate the effectiveness of TAVI as routine therapeutic procedure in the treatment of patients with low surgical risk AS

MULTIPLE CERVICAL CORD COMPRESSIONS IN PSORIATIC-ARTHRITIS

Coexistent atlantoaxial subluxation (AAS) and subaxial spondylitic changes led to multiple cervical cord compressions in a psoriatic arthritis (PA) patient. Magnetic resonance imaging and myelography were unable to define exactly which cervical lesion was responsible for neurological symptoms. After surgical intervention for the worsening of bulbar symptoms, clinical course of neurological complaints suggested that neurological involvement was due only to anterior/vertical AAS

LUPUS-ERYTHEMATOSUS PANNICULITIS - AN IMMUNOHISTOCHEMICAL STUDY

An immunohistochemical study on a case of lupus erythematosus panniculitis (LEP), without discoid lupus erythematosus (DLE) or systemic lupus erythematosus (SLE) signs, showed that the cells in skin infiltrates were immunologically committed lymphocytes (OKT4, OKT8, OKT11 and HLA-DR positive cells) and elements of the monocyte-macrophage lineage (Leu M3 and Leu M5 positive). No immunophenotypically identifiable B-lymphocytes were seen. Immunofluorescent IgG, IgM, C3 and C4 deposits were found in blood vessel walls of the deep dermis. These findings, similar to that described in the skin changes of SLE and DLE, suggest that immunological mechanisms are operative in localized LEP, where the dermal lesions are the only expression of the disease

ONE-YEAR TREATMENT WITH LOW-DOSE METHOTREXATE IN RHEUMATOID-ARTHRITIS - EFFECT ON CLASS-SPECIFIC RHEUMATOID FACTORS

We evaluated the effect of a one-year treatment of low dose methotrexate (MTX) on class specific rheumatoid factors in 27 patients with rheumatoid arthritis (RA). Enzyme-linked immunosorbent assay (ELISA) showed after 6 and 12 months a significant reduction of IgM-RF, IgA-RF and IgG-RF levels from the baseline values. During MTX treatment, changes of each RF isotype were not correlated with any other isotype and its corresponding immunoglobulin changes. Moreover, immunological changes were not related to the improvement of clinical parameters. Our results showed that low dose MTX can specifically affect levels of RF isotypes, which are involved in the immune pathogenesis of RA