Pro/Anti-Inflammatory Cytokine Imbalance in Postischemic Left Ventricular Remodeling

Objectives. Cytokines play an important role in left ventricular remodeling consequent to myocardial ischemia. The aim of this study was to correlate cytokine production and lymphocyte apoptosis to post-ischemic left ventricular remodeling in patients affected by acute myocardial infarction (AMI) undergoing primary cutaneous angioplasty (PCI). Methods. In 40 patients, affected by AMI and undergoing PCI, we evaluated peripheral blood mononuclear cells (PBMCs), tumor necrosis factor-alpha (TNF-α) and interleukin 10 (IL10) production and apoptosis on day 1, day 3, day 7, 1 month and 6 months after PCI. Patients were divided into two subgroups of remodeling or not remodeling by echocardiographic criteria. Results. In the subgroup of remodeling patients, at each timepoint TNF-α production was increased significantly in comparison with the subgroup of not remodeling patients. IL10 production was statistically lower in remodeling subjects than in not remodeling ones 1 and 6 months after reperfusion. There were no differences between the two groups as regards lymphomonocyte apoptosis. Conclusions. We found an increased production of pro-inflammatory cytokine TNF-α and a corresponding decrease of anti-inflammatory/regulatory cytokine IL10 in remodeling patients and we concluded that this cytokine imbalance resulted in pro-inflammatory effects which might contribute to the progression of left ventricular remodeling

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

REFRACTORY TAKAYASU ARTERITIS SUCCESSFULLY TREATED WITH INFLIXIMAB

Takayasu arteritis (TA) is a chronic inflammatory disease of large arteries which progressively develop stenosis, occlusion or aneurismal degeneration. Proinflammatory cytokines and, among these, tumor necrosis factor-alpha (TNF-alpha) are increased and play a pathogenetic role in the development of disease. Conventional therapy often fails to determine clinical remission and, in these cases, pathogenetic strategies with anti-TNF-alpha drugs have been proposed. Infliximab is a human-murine chimeric monoclonal antibody that specifically binds to and neutralizes soluble TNF-alpha. It is an effective treatment for rheumatoid arthritis, spondyloarthritis, Crohn's disease and ulcerative colitis and it has been recently proposed for the treatment of TA in patients refractory to conventional therapy. Here we report the case of a patient affected by Takayasu arteritis unresponsive to conventional therapy who was then treated with infliximab and obtained a clinical remission of the disease

Inhibition of maturation of human monocyte-derived dendritic cells in a patient with Mycobacterium avium infection.

Mycobacterium avium complex is a facultative intracellular pathogen that can cause pulmonary disease in immunocompromised individuals. Dendritic cells (DCs) play a central role in protective immunity against mycobacteria. Mycobacterium avium complex infects DCs but does not impair in vitro infected monocytes differentiation into DCs. A 54-year old woman affected by chronic graft-versus-host-disease (cGVHD) was referred to our Division of Dermatology. Immature DCs were generated from her monocytes. One week later she was hospitalized due to a lung infection with Mycobacterium avium complex. Monocyte-derived DCs during Mycobacterium avium infection expressed low levels of CD1a and CD80 as determined by flow cytometry. They also expressed high levels of CD83 and CD86, and when stimulated with LPS for 24 hrs they slightly up-regulated CD83 and did not produce IL12. When monocyte-derived DCs were obtained from the patient after having recovered from the Mycobacterium avium complex infection, they expressed normal levels of CD1a and CD80 and were negative both for CD83 and for CD86. IL12 production in response to LPS was restored. Inhibition of DC maturation by the in vivo infection with Mycobacterium avium may be an immune-evasion mechanism used by the pathogen because incompletely matured DCs may not activate effector T cells efficiently in vivo

Dyslipidemias and fibrinolysis.

BACKGROUND: The relation between fibrinolysis and cardiovascular disease is an open debate. Fibrinolysis is related to endothelial function and presents many molecular links with platelet and coagulation activity. Furthermore, reduced fibrinolysis has been reported in several dysmetabolic conditions. METHODS: To detect mechanisms linking dyslipidemias and fibrinolysis we evaluated 75 subjects (42 males, 33 females, 20 hypercholesterolemic, 20 hypertriglyceridemic or 20 with mixed hyperlipoproteinemia, 15 with isolated low HDL-cholesterol). Plasminogen activator inhibitor (PAI)-1, tissue-type plasminogen activator activity and plasmin-antiplasmin complexes (PAP) were determined at baseline and after the venous occlusion test. We also measured D-dimer, lipid pattern, soluble E-selectin, platelet surface P-selectin, prothrombin fragments 1 + 2 (F1 + 2), lipoprotein(a), factor VII, von Willebrand factor, plasma insulin, fibrinogen, homocysteine, thrombin activable fibrinolysis inhibitor (TAFI) activity, thrombomodulin, factor XIII, urokinase-type plasminogen activator. RESULTS: Hypertriglyceridemic patients were found to have lower PAP and D-dimer and higher PAI-1 serum levels (baseline and venous occlusion test, p < 0.001 and p < 0.01) compared to hypercholesterolemic and control subjects (p < 0.01, p < 0.001). P-selectin, F1 + 2 and TAFI were significantly increased only in hypercholesterolemic subjects (p < 0.001) and associated with reduced PAP and D-dimer, showing a linear relation with LDL-cholesterol levels (p < 0.01, r = -0.62 and p < 0.01, r = -0.59). PAI-1 activity was not different with respect to controls (baseline p = 0.59, venous occlusion test p = 0.42). Serum levels of von Willebrand factor were significantly increased in hypertriglyceridemic/low HDL subjects compared to hypercholesterolemics (p < 0.01). CONCLUSIONS: Impaired fibrinolysis in subjects with hypertriglyceridemia/low HDL-cholesterol is associated with increased serum levels of PAI-1 whereas enhanced thrombin generation and TAFI hyperactivity are the main findings in hypercholesterolemia. Such data may suggest the opportunity of evaluating several fibrinolytic factors when studied as prognostic factors in diverse dyslipidemias

Genetic influence in antithrombotic actions of atorvastatin in hypercholesterolaemia

BACKGROUND:Recent data indicate that statins could offer coronary artery disease (CAD) benefit even by mechanisms beyond lipid lowering. Genetic influence has been shown for some antithrombotic actions of statins via oxidized-low-density lipoprotein cholesterol (ox-LDL) receptors and nitric oxide synthase (NOS) activity modulation. The present study was designed to evaluate the influence of ox-LDL lectin-like receptor-1 (LOX-1) and NOS polymorphisms in the incidence of cardiovascular events in pure hypercholesterolaemic subjects during statin treatment. MATERIALS AND METHODS:A prospective 4-year study involving 1039 event-free subjects (643 males, 396 females) treated with atorvastatin (10-40 mg day(-1)) to reach the appropriate Adult Treatment Panel-III LDL target of 3.36 mmol L(-1). Enrolled subjects were evaluated every 6 months or at a clinical event. LOX-1 3'UTR/T-C and NOS G894T polymorphisms were detected by allelic discrimination assays (polymerase chain reaction), lipid profile by enzymatic-colorimetric method, ox-LDL by enzyme linked immunosorbent assay, platelet activation by P-selectin (P-sel) expression (FACScan), NOS activity (by intracellular citrullin recovery) and homocysteine (high performance liquid chromatography), C-reactive protein (CRP) by sensitive nephelometric technique. RESULTS:LOX-1 3'UTR/T showed the strongest association with events in the whole cohort with respect to each other variable including LDL reduction and NOS G894T (OR 4.90, 95% CI 3.19-6.98, P < 0.00001). Smoking influenced events in LDL-targeted subjects (P < 0.0001). Ox-LDL and P-sel were better indicators than LDL or other variables according to 3'UTR/C genotype regardless of the magnitude of LDL reduction (OR 4.21, 95% CI 2.29-6.70 P < 0.0001). CONCLUSIONS:LOX-1 polymorphisms could influence statin effectiveness in CAD prevention by induction of sensitivity to antithrombotic mechanisms such as antiplatelet activit

A proteomic approach to investigate the role of the MECP2 gene mutation in Rett syndrome redox regulatory pathways

Mutations in the X-linked methyl-CpG-binding 2 (MECP2) gene lead to Rett Syndrome (RTT; OMIM 312750), a devasting neurodevelopmental disorder. RTT clinical manifestations are complex and with different degrees of severity, going from autistic-like behavior to loss of acquired speech, motor skills and cardiac problems. Furthermore, the correlation between the type of MECP2 mutation and the clinical phenotype is still not fully understood.Contextually, different genotypes can differently affect the patient's phenotype and omics methodologies such as proteomics could be an important tool for a molecular characterization of genotype/phenotype correlation. The aim of our study was focused on evaluating RTT oxidative stress (OS) responses related to specific MECP2 gene mutations by using proteomics and bioinformatics approaches.Primary fibroblasts isolated from patients affected by R133C and R255x mutations were compared to healthy controls (HC).After clustering primary dermal fibroblasts based on their specific MECP2 mutations, fibroblast-derived pro-tein samples were qualitative and quantitative analyzed, using a label free quantification (LFQ) analysis by mass spectrometry (MS), achieving a preliminary correlation for RTT genotype/phenotype. Among the identified proteins involved in redox regulation pathways, NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1) was found to be absent in R255x cells, while it was present in R133C and in HC fibroblasts. Moreover, NQO1 aberrant gene regulation was also confirmed when cells were challenged with 100 mu M hydrogen peroxide (H2O2).In conclusion, by employing a multidisciplinary approach encompassing proteomics and bioinformatics an-alyses, as well as molecular biology assays, the study uncovered phenotypic responses linked to specific MECP2 gene mutations.These findings contribute to a better understanding of the complexity of RTT molecular pathways, confirming the high heterogeneity among the patients

Psychosine-induced apoptosis and cytokine activation in immune peripheral cells of Krabbe patients.

Globoid cell leukodystrophy or Krabbe disease (KD), is a hereditary disorder caused by galactosylceramidase deficiency. Progressive accumulation of psychosine is considered to be the critical pathogenetic mechanism of cell death in the Krabbe brain. Psychosine mechanism of action has not been fully elucidated. It seems to induce apoptosis in oligodendrocytes through a mitochondrial pathway and to up-regulate inflammatory cytokines production resulting in oligodendrocyte loss. Our aim was to evaluate the role of psychosine in apoptotic cell death and inflammatory response in a group of patients affected by KD using peripheral blood lymphocytes (PBLs) and peripheral blood mononuclear cells (PBMCs) as a cellular model. PBLs from KP and healthy controls were exposed to 20 microM psychosine and analysed by flow cytometry, agarose gel electrophoresis and fluorescence microscopy. Our results showed that psychosine induces apoptosis in PBLs through a mitochondrial pathway, but the apoptotic response was quite low especially KP. The role of psychosine in the up-regulation of cytokines (TNFalpha, IL8 and MCP1) has been evaluated by ELISA in PBMCs from KP and controls after stimulation with LPS and phytohemagglutinin. Both in basal condition and after LPS stimulation, cells from KP showed a significant increase in TNF-alpha production, reduced MCP1 levels and no modification in IL8. These results indicate that lymphomonocytes from KP had a basal proinflammatory pattern that was amplified by psychosine. In conclusion, the reduced apoptotic response and the atypical cytokine production observed in our experiments, suggest an involvement of inflammatory pattern in immune peripheral cells of KP