PCSK9 Biology and Its Role in Atherothrombosis

It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action

Atypical Presentation of Acute Coronary Syndrome-Not ST Elevation: A Case Report

We describe the unexpected case of a 70-year-old man, with medical history of ischemic heart disease and surgery for aneurysm of abdominal aorta, who comes to the emergency department complaining of low-back pain without other symptoms or signs of organic failure. After a few hours we see a deterioration of physical conditions with pulmonary oedema, increase of blood pressure, changing in the ECG pattern, and worsening of left ventricular function with progressive increase of biomarkers for myocardial necrosis. So this pain has revealed the premature symptom of an acute coronary syndrome (ACS). After a short time a subsequent cardiac arrest complicates the clinical situation. After resuscitation, the patient undergoes successfully to coronary angiography and performed a percutaneous transluminal coronary angioplasty (PTCA)

Multicenter randomized, double-blind controlled trial to evaluate the efficacy of laser therapy for the treatment of severe oral mucositis induced by chemotherapy in children: LaMPO RCT

OBJECTIVES: To demonstrate the efficacy of laser photobiomodulation (PBM) compared to that of placebo on severe oral mucositis (OM) in pediatric oncology patients. The primary objective was the reduction of OM grade (World Health Organization [WHO] scale) 7 days after starting PBM. Secondary objectives were reduction of pain, analgesic consumption, and incidence of side effects. METHODS: One hundred and one children with WHO grade > 2 chemotherapy-induced OM were enrolled in eight Italian hospitals. Patients were randomized to either PBM or sham treatment for four consecutive days (days +1 to +4). On days +4, +7, and +11, OM grade, pain (following a 0-10 numeric pain rating scale, NRS) and need for analgesics were evaluated by an operator blinded to treatment. RESULTS: Fifty-one patients were allocated to the PBM group, and 50 were allocated to the sham group. In total, 93.7% of PBM patients and 72% of sham patients had OM grade < 3 WHO on day +7 (P = 0.01). A significant reduction of pain was registered on day +7 in the PBM versus sham group (NRS 1 [0-3] vs. 2.5 [1-5], P < 0.006). Reduced use of analgesics was reported in the PBM group, although it was not statistically significant. No significant adverse events attributable to treatment were recorded. CONCLUSIONS: PBM is a safe, feasible, and effective treatment for children affected by chemotherapy-induced OM, as it accelerates mucosal recovery and reduces pain

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2

Prothrombotic Phenotype in COVID-19: Focus on Platelets

COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients

Impact of Physical Exercise on Platelets: Focus on Its Effects in Metabolic Chronic Diseases

Chronic disorders are strongly linked to cardiovascular (CV) diseases, and it is unanimously accepted that regular exercise training is a key tool to improving CV risk factors, including diabetes, dyslipidemia, and obesity. Increased oxidative stress due to an imbalance between reactive oxygen species production and their scavenging by endogenous antioxidant capacity is the common ground among these metabolic disorders, and each of them affects platelet function. However, the correction of hyperglycemia in diabetes and lipid profile in dyslipidemia as well as the lowering of body weight in obesity all correlate with amelioration of platelet function. Habitual physical exercise triggers important mechanisms related to the exercise benefits for health improvement and protects against CV events. Platelets play an important role in many physiological and pathophysiological processes, including the development of arterial thrombosis, and physical (in)activity has been shown to interfere with platelet function. Although data reported by studies carried out on this topic show discrepancies, the current knowledge on platelet function affected by exercise mainly depends on the type of applied exercise intensity and whether acute or habitual, strenuous or moderate, thus suggesting that physical activity and exercise intensity may interfere with platelet function differently. Thus, this review is designed to cover the aspects of the relationship between physical exercise and vascular benefits, with an emphasis on the modulation of platelet function, especially in some metabolic diseases

Utilità della ripresa fotografica a colori della papilla ottica nel glaucoma cronico semplice: nostre considerazioni su casi particolari

Scopo del presente lavoro è di evidenziare l’utilità clinica della fotografia della papilla ottica nella gestione del follow-up di pazienti affetti da glaucoma cronico semplice, soprattutto in casi clinici particolari. Presso il centro Glaucoma della II Divisione della Clinica Oculistica dell’Università “La Sapienza” di Roma, gli Autori hanno eseguito la ripresa fotografica in gruppi di pazienti affetti da glaucoma cronico semplice o in accertamento diagnostico che presentano malformazioni papillari, aree di atrofia corioretinica peripapillare, dischi ottici con rapporto cup/disk alterato ( 0,3), asimmetrie significative del rapporto cup/disk (&gt; 0,2) o semplicemente perchè monoculi o di giovane età. Spesso i pazienti presentano contemporaneamente più criteri di inclusione, rafforzando la necessità di eseguire in questi casi tale indagine. In ognuno di questi gruppi è presente una problematica clinica, per la quale lo studio dello stato papillare gioca un ruolo fondamentale. La fotografia della papilla ottica consente di documentare lo stato attuale papillare e di effettuare una valutazione obiettiva da parte di più operatori, rappresentando un indispensabile ausilio per il monitoraggio cronologico del paziente. L’analisi fiotografica della papilla ottica si pone alla stregua delle più moderne metodiche di indagine dello stato papillare per la semplicità di esecuzione, l’economicità, la ripetibilità e la non invasività; inoltre rappresenta la base di un’ulteriore analisi morfometrica. In conclusione, la fotografia della papilla ottica è una pratica estensibile all’intera popolazione glaucomatosa, o quanto meno a casi particolari, che alla utilità clinica associa la possibilità di effettuare un’opera di educazione sanitaria specifica, migliora il rapporto “paziente-malattia” e agevola anche la compliance terapeutica