Unveiling IL-33/ST2 Pathway Unbalance in Cardiac Remodeling Due to Obesity in Zucker Fatty Rats.

Obesity is an epidemic condition linked to cardiovascular disease severity and mortality. Fat localization and type represent cardiovascular risk estimators. Importantly, visceral fat secretes adipokines known to promote low-grade inflammation that, in turn, modulate its secretome and cardiac metabolism. In this regard, IL-33 regulates the functions of various immune cells through ST2 binding and-following its role as an immune sensor to infection and stress-is involved in the pro-fibrotic remodeling of the myocardium. Here we further investigated the IL-33/ST2 effects on cardiac remodeling in obesity, focusing on molecular pathways linking adipose-derived IL-33 to the development of fibrosis or hypertrophy. We analyzed the Zucker Fatty rat model, and we developed in vitro models to mimic the adipose and myocardial relationship. We demonstrated a dysregulation of IL-33/ST2 signaling in both adipose and cardiac tissue, where they affected Epac proteins and myocardial gene expression, linked to pro-fibrotic signatures. In Zucker rats, pro-fibrotic effects were counteracted by ghrelin-induced IL-33 secretion, whose release influenced transcription factor expression and ST2 isoforms balance regulation. Finally, the effect of IL-33 signaling is dependent on several factors, such as cell types' origin and the balancing of ST2 isoforms. Noteworthy, it is reasonable to state that considering IL-33 to have a unique protective role should be considered over-simplistic.

A Wide-Proteome Analysis to Identify Molecular Pathways Involved in Kidney Response to High-Fat Diet in Mice.

The etiopathogenesis of obesity-related chronic kidney disease (CKD) is still scarcely understood. To this aim, we assessed the effect of high-fat diet (HF) on molecular pathways leading to organ damage, steatosis, and fibrosis. Six-week-old male C57BL/6N mice were fed HF diet or normal chow for 20 weeks. Kidneys were collected for genomic, proteomic, histological studies, and lipid quantification. The main findings were as follows: (1) HF diet activated specific pathways leading to fibrosis and increased fatty acid metabolism; (2) HF diet promoted a metabolic shift of lipid metabolism from peroxisomes to mitochondria; (3) no signs of lipid accumulation and/or fibrosis were observed, histologically; (4) the early signs of kidney damage seemed to be related to changes in membrane protein expression; (5) the proto-oncogene MYC was one of the upstream transcriptional regulators of changes occurring in protein expression. These results demonstrated the potential usefulness of specific selected molecules as early markers of renal injury in HF, while histomorphological changes become visible later in obesity-related CDK. The integration of these information with data from biological fluids could help the identification of biomarkers useful for the early detection and prevention of tissue damage in clinical practice.

Intra-erythrocytes magnesium deficiency could reflect cognitive impairment status due to vascular disease: a pilot study.

BACKGROUND AND AIMS: Magnesium is a fundamental cation that regulates neuronal transmission, protein synthesis, energy metabolism. Magnesium deficiency mostly affects nervous and cardiovascular systems determining weakness, tremors, seizure and arrhythmias. This condition retains also a role in memory function and neuronal plasticity. Importantly magnesium deficiency could remain latent and asymptomatic resulting a risk factor for cardiovascular disease. In this sense we aim to determine magnesium status in patient presenting cognitive impairment of vascular origin. METHODS: 21 healthy subjects and 27 patients presenting vascular cognitive impairment were included in this study. Both plasma and intraerythrocitary magnesium level were measured to detect magnesium deficiency and cognitive performance was evaluated trough Mini Mental State Evaluation (MMSE). RESULTS: Here we showed that patients presenting vascular cognitive impairment present intraerythrocitary magnesium level lower than age-matched healthy subjects. To note their plasma magnesium resulted within reference limit. CONCLUSION: We suggest that intracellular magnesium laboratory measurement is needed to detect occult magnesium deficiency in population at risk. Magnesium supplementation could represent an adjuvant for healthy aging in high risk population.

Osteopontin: The Molecular Bridge between Fat and Cardiac-Renal Disorders.

Osteopontin (OPN) is a multifaceted matricellular protein, with well-recognized roles in both the physiological and pathological processes in the body. OPN is expressed in the main organs and cell types, in which it induces different biological actions. During physiological conditioning, OPN acts as both an intracellular protein and soluble excreted cytokine, regulating tissue remodeling and immune-infiltrate in adipose tissue the heart and the kidney. In contrast, the increased expression of OPN has been correlated with the severity of the cardiovascular and renal outcomes associated with obesity. Indeed, OPN expression is at the "cross roads" of visceral fat extension, cardiovascular diseases (CVDs) and renal disorders, in which OPN orchestrates the molecular interactions, leading to chronic low-grade inflammation. The common factor associated with OPN overexpression in adipose, cardiac and renal tissues seems attributable to the concomitant increase in visceral fat size and the increase in infiltrated OPN+ macrophages. This review underlines the current knowledge on the molecular interactions between obesity and the cardiac-renal disorders ruled by OPN.

Correlative Study on Impaired Prostaglandin E2 Regulation in Epicardial Adipose Tissue and its Role in Maladaptive Cardiac Remodeling via EPAC2 and ST2 Signaling in Overweight Cardiovascular Disease Subjects.

There is recent evidence that the dysfunctional responses of a peculiar visceral fat deposit known as epicardial adipose tissue (EAT) can directly promote cardiac enlargement in the case of obesity. Here, we observed a newer molecular pattern associated with LV dysfunction mediated by prostaglandin E2 (PGE2) deregulation in EAT in a cardiovascular disease (CVD) population. A series of 33 overweight CVD males were enrolled and their EAT thickness, LV mass, and volumes were measured by echocardiography. Blood, plasma, EAT, and SAT biopsies were collected for molecular and proteomic assays. Our data show that PGE2 biosynthetic enzyme (PTGES-2) correlates with echocardiographic parameters of LV enlargement: LV diameters, LV end diastolic volume, and LV masses. Moreover, PTGES-2 is directly associated with EPAC2 gene (r = 0.70, p < 0.0001), known as a molecular inducer of ST2/IL-33 mediators involved in maladaptive heart remodelling. Furthermore, PGE2 receptor 3 (PTEGER3) results are downregulated and its expression is inversely associated with ST2/IL-33 expression. Contrarily, PGE2 receptor 4 (PTGER4) is upregulated in EAT and directly correlates with ST2 molecular expression. Our data suggest that excessive body fatness can shift the EAT transcriptome to a pro-tissue remodelling profile, may be driven by PGE2 deregulation, with consequent promotion of EPAC2 and ST2 signalling.

Correlational study on altered epicardial adipose tissue as a stratification risk factor for valve disease progression through IL-13 signaling.

AIMS: Genetic and environmental factors all interact in the risk of progression of valvular dysfunctions. Previous studies reported a relation between valve diseases and epicardial adipose tissue (EAT) thickness. The aim of this study was to verify the possible relationship between the molecular pattern of EAT related to IL-13 fibrogenic cytokine expression and valve dysfunction. METHODS AND RESULTS: A valvular heart disease (VHD) population was stratified according to their median EAT thickness (7 mm). The molecular expression of IL-13 in EAT is directly related to the molecular expression of genes associated with extracellular matrix (ECM) turnover, macrophage infiltration and promotion of the formation of ectopic calcific nodules involved in aorta coarctation and calcification. CONCLUSION: IL-13 gene expression in altered EAT is directly related to the expression of genes involved in ECM turnover and the formation of ectopic calcific nodules, suggesting measurements of EAT as a stratification risk factor for valve instability in the VHD patients.

Lag-time in Alzheimer's disease patients: a potential plasmatic oxidative stress marker associated with ApoE4 isoform.

In the brain, Oxidative Stress (OS) contribute to structural and functional changes associated with vascular aging, such as endothelial dysfunction, extracellular matrix degradation, resulting in age-related reduced vasodilatation in response to agonists. For this reason, OS is considered a key factor in Alzheimer's Disease (AD) development and recent evidence correlated oxidative stress with vascular lesion in the pathogenesis of AD, but the mechanism still need to be fully clarified. The etiology of AD is still not completely understood and is influenced by several factors including Apolipoprotein E (ApoE) genotype. In particular, the Apo ε4 isoform is considered a risk factor for AD development. This study was aimed to evaluate the possible relationship between three plasmatic OS marker and Apo ε4 carrier status. Plasmatic soluble receptor for advanced glycation end products (sRAGE) levels, plasma antioxidant total defenses (by lag-time method) and plasmatic Reactive Oxygen species (ROS) levels were evaluated in 25 AD patients and in 30 matched controls. ROS were significantly higher while plasma antioxidant total defenses and sRAGE levels were significantly lower in AD patients compared to controls. In AD patients lag-time values show a significant positive linear correlation with sRAGE levels and a (even not significant) negative correlation with ROS levels. Lag-time is significantly lower in ε4 carrier (N = 13) than in ε4 non-carrier (N = 12). Our result confirms the substantial OS in AD. Lag-time levels showed a significant positive correlation with sRAGE levels and a significant association with ε4 carrier status suggesting that plasmatic lag-time evaluation can be considered as a potential useful OS risk marker in AD.

Levels of uric acid in erectile dysfunction of different aetiology.

Erectile dysfunction is a common disease characterized by endothelial dysfunction. The aetiology of ED is often multifactorial but evidence is being accumulated in favor of the proper function of the vascular endothelium that is essential to achieving and maintaining penile erection. Uric acid itself causes endothelial dysfunction via decreased nitric oxide production. This study aims to evaluate the serum uric acid (SUA) levels in 180 ED patients, diagnosed with the International Index of Erectile Function-5 (IIEF-5) and 30 non-ED control. Serum uric acid was analyzed with a commercially available kit using ModularEVO (Roche, Monza, Italy). Within-assay and between-assay variations were 3.0% and 6.0%, respectively. Out of the ED patients, 85 were classified as arteriogenic (A-ED) and 95 as non-arteriogenic (NA-ED) with penile-echo-color-Doppler. Uric acid levels (median and range in mg/dL) in A-ED patients (5.8, 4.3-7.5) were significantly higher (p < .001) than in NA-ED patients (4.4, 2.6-5.9) and in control group (4.6, 3.1-7.2). There was a significant difference (p < .001) between uric acid levels in patients with mild A-ED (IIEF-5 16-20) and severe/complete A-ED (IIEF-5 ≤ 10) that were 5.4 (range 4.3-6.5) mg/dL and 6.8 (range 6.4-7.2) mg/dL, respectively. There was no difference between the levels of uric acid in patients with different degree of NA-ED. Our findings reveal that SUA is a marker of ED but only of ED of arteriogenic aetiology.

Increased Levels of sRAGE in Diabetic CKD-G5D Patients: A Potential Protective Mechanism against AGE-Related Upregulation of Fibroblast Growth Factor 23 and Inflammation.

Advanced glycation end products (AGEs) may induce cardiac remodeling in kidney disease by promoting fibroblast growth factor 23 (FGF-23) expression. Since AGEs are increased in diabetes mellitus (DM), our first aim was to evaluate the existence of any potential association between AGEs, FGF-23, inflammation, and increased cardiovascular risk in DM patients on dialysis (CKD-G5D). Secondarily, we explored the potential role of the soluble receptor for AGEs (sRAGE) as a marker of heart failure. Levels of glycated albumin (GA), sRAGE, c-terminal FGF-23 (cFGF-23), brain natriuretic peptide (BNP), and inflammatory mediators were compared between DM and non-DM CKD-G5D patients. The levels of sRAGE, cFGF-23, BNP, and proinflammatory markers were over the ranges of normality in both DM and non-DM groups. Only GA and sRAGE levels were increased in DM compared to non-DM patients. Plasma levels of sRAGE and CRP were the only independent predictors of BNP concentration. In conclusion, in DM CKD-G5D patients, sRAGE appeared to be a marker of cardiac remodeling. Indeed, its increase could be a potential protective mechanism against the increased risk of cardiovascular complications related to AGEs and inflammation. The causal relationship between sRAGE and cardiovascular risk in these patients needs to be further confirmed by mechanistic studies.

Osteocalcin as a potential risk biomarker for cardiovascular and metabolic diseases.

Clear evidence supports a role for circulating and locally-produced osteocalcin (OC) in the pathophysiology of cardiovascular (CV) lesions and CV risk, also in combination with metabolic changes, including type 2 diabetes mellitus (T2DM). Reduced plasma OC levels are associated with greater incidence of pathological CV changes, like arterial and valvular calcification, coronary and carotid atherosclerosis and increased carotid intima-media thickness. The actual relationship between OC levels and incidence of major CV events is, however, still unclear. Moreover, reduced circulating OC levels have been mostly associated with insulin resistance, metabolic syndrome or T2DM, indicating relevant OC actions on pancreatic ß-cells and insulin secretion and activity. Based on these observations, this review article will attempt to summarize the current evidence on the potential usefulness of circulating OC as a biomarker for CV and metabolic risk, also evaluating the currently open issues in this area of research.

Association with meteo-climatological factors and daily emergency visits for renal colic and urinary calculi in Cuneo, Italy. A retrospective observational study, 2007-2010.

The incidence of nephrolithiasis is rising worldwide, especially in women and with increasing age. Incidence and prevalence of kidney stones are affected by genetic, nutritional, and environmental factors. The aim of this study is to investigate the link between various meteorological factors (independent variables) and the daily number of visits to the Emergency Department (ED of the S. Croce and Carle Hospital of Cuneo for renal colic (RC) and urinary stones (UC) as the dependent variable over the years 2007-2010.The Poisson generalized regression models (PGAMs) have been used in different progressive ways. The results of PGAMs (stage 1) adjusted for seasonal and calendar factors confirmed a significant correlation (p < 0.03) with the thermal parameter. Evaluation of the dose-response effect [PGAMs combined with distributed lags nonlinear models (DLNMs)-stage 2], expressed in terms of relative risk (RR) and cumulative relative risk (RRC), indicated a relative significant effect up to 15 lag days of lag (RR > 1), with a first peak after 5 days (lag ranges 0-1, 0-3, and 0-5) and a second weak peak observed along the 5-15 lag range days. The estimated RR for females was significant, mainly in the second and fourth age group considered (19-44 and >65 years): RR for total ED visits 1.27, confidence interval (CI) 1.11-1.46 (lag 0-5 days); RR 1.42, CI 1.01-2.01 (lag 0-10 days); and RR 1.35, CI 1.09-1.68 (lag 0-15 days). The research also indicated a moderate involvement of the thermal factor in the onset of RC caused by UC, exclusively in the female sex. Further studies will be necessary to confirm these results.

Effect of an isocaloric diet containing fiber-enriched flour on anthropometric and biochemical parameters in healthy non-obese non-diabetic subjects.

We studied the effect of soluble fiber-enriched products on anthropometric and biochemical variables in 30 healthy non-obese, non-diabetic subjects. This was a randomized, controlled crossover, single-blind, dietary intervention study performed for 8 weeks. Subjects received an isocaloric diet with fiber-enriched products for the first 4 weeks and with regular flour products for the following 4 weeks, or vice versa. Weight, height, measures of fat distribution (waist, hip circumference), glucose, insulin and triglycerides were measured at baseline, after 4 and 8 weeks of intervention. BMI and insulin sensitivity indices were calculated. Weight and BMI decreased in the first period of isocaloric diet in both groups, regardless of the type of flour consumed (weight p<0.01, p<0.001 respectively; BMI p = 0.01, p<0.001 respectively). At the end of the 8 weeks, weight and BMI further decreased in the group consuming the fiber-enriched diet (p<0.01). Insulin resistance, estimated with the Homeostasis Model Assessment index and the Lipid Accumulation Product index, improved in all subjects after the fiber-enriched flour diet (p = 0.03, p = 0.02, respectively). In conclusion, an isocaloric diet supplemented with fiber-enriched products may improve measures of fatness and insulin sensitivity in healthy non-obese non-diabetic subjects. We might hypothesize a similar effect also in subjects with metabolic abnormalities.

Low heart-type fatty acid binding protein level during aging may protect down syndrome people against atherosclerosis.

BACKGROUND: Aging is considered an important independent risk factor for atherosclerosis. Down syndrome people (DS) display an accelerated aging process compared to healthy subjects, anyway they are relatively resistant to developing atherosclerosis. The mechanisms involved in such protective effect are not well known. Since heart-type fatty acid binding protein (H-FABP) is a protein involved in the transport of fatty acids and it has been recently correlated with the presence of atherosclerosis, we aimed to measure H-FABP level both in DS and in healthy subjects during aging to evaluate the association between this molecule, aging and atherosclerosis. FINDINGS: We quantified plasmatic H-FABP level in three groups of male DS and age-matched healthy subjects (children, age 2-14 years; adults, age 20-50 years; elderly, > 60 years) using a biochip array analyzer. We observed that aging is associated with increased H-FABP level in healthy subjects but not in DS which display both the same protein level in the different ages of life and have also lower level compared to their age-matched healthy subjects. CONCLUSION: Reduced H-FABP level during aging in DS may play a protective role against atherosclerosis. The potential involvement of H-FABP in the relationship between aging, atherosclerosis and development of coronary artery disease needs further investigations.

Papaver somniferum in seventeenth century (Italy): archaeotoxicological study on brain and bone samples in patients from a hospital in Milan.

In this paper, we present the results of toxicological analyses of preserved brain tissue and bone samples from the remains of the seventeenth century patients of the Ospedale Maggiore, the main hospital in Milan and one of the most innovative hospitals in Europe from the Renaissance period. Beneath it, the crypt functioned as the burial place for the deceased of the hospital. In this multidisciplinary study of the remains, toxicological analyses in particular were performed with HPLC-MS/MS on different biological samples from nine individuals. Anthropological, paleopathological, histological, radiological examinations and radiocarbon dating were also carried out. As a result, archeotoxicological analyses revealed the presence of codeine, morphine, noscapine and papaverine, derived from Papaver somniferum, a plant present in the hospital pharmacopeia used as a narcotic, analgesic, astringent, coagulant, and antitussive agent. Such analyses have shed light on the pharmacological therapies administered to the patients near the time of death and have implemented our knowledge of medical treatment and drug administration in the 1600's.

Human epicardial adipose tissue expresses glucose-dependent insulinotropic polypeptide, glucagon, and glucagon-like peptide-1 receptors as potential targets of pleiotropic therapies.

AIMS: Human epicardial adipose tissue (EAT) plays a crucial role in the development and progression of coronary artery disease, atrial fibrillation, and heart failure. Microscopically, EAT is composed of adipocytes, nerve tissues, inflammatory, stromovascular, and immune cells. Epicardial adipose tissue is a white adipose tissue, albeit it also has brown fat-like or beige fat-like features. No muscle fascia divides EAT and myocardium; this allows a direct interaction and crosstalk between the epicardial fat and the myocardium. Thus, it might be a therapeutic target for pharmaceutical compounds acting on G-protein-coupled receptors, such as those for glucose-dependent insulinotropic polypeptide (GIP), glucagon (GCG), and glucagon-like peptide-1 (GLP-1), whose selective stimulation with innovative drugs has demonstrated beneficial cardiovascular effects. The precise mechanism of these novel drugs and their tissue and cellular target(s) need to be better understood. We evaluate whether human EAT expresses GIP, GCG, and GLP-1 receptors and whether their presence is related to EAT transcriptome. We also investigated protein expression and cell-type localization specifically for GIP receptor (GIPR) and glucagon receptor (GCGR). METHODS AND RESULTS: Epicardial adipose tissue samples were collected from 33 patients affected by cardiovascular diseases undergoing open heart surgery (90.9% males, age 67.2 ± 10.5 years mean ± SD). Microarray and immunohistochemistry analyses were performed. Microarray analysis showed that GIPR and GCGR messenger ribonucleic acids (mRNAs) are expressed in EAT, beyond confirming the previously found GLP-1 [3776 ± 1377 arbitrary unit (A.U.), 17.77 ± 14.91 A.U., and 3.41 ± 2.27 A.U., respectively]. The immunohistochemical analysis consistently indicates that GIPR and GCGR are expressed in EAT, mainly in macrophages, isolated, and in crown-like structures. In contrast, only some mature adipocytes of different sizes showed cytoplasmic immunostaining, similar to endothelial cells and pericytes in the capillaries and pre-capillary vascular structures. Notably, EAT GIPR is statistically associated with the low expression of genes involved in free fatty acid (FFA) oxidation and transport and those promoting FFA biosynthesis and adipogenesis (P < 0.01). Epicardial adipose tissue GCGR, in turn, is related to genes involved in FFA transport, mitochondrial fatty acid oxidation, and white-to-brown adipocyte differentiation, in addition to genes involved in the reduction of fatty acid biosynthesis and adipogenesis (P < 0.01). CONCLUSIONS: Having reported the expression of the GLP-1 receptor previously, here, we showed that GIPR and GCGR similarly present at mRNA and protein levels in human EAT, particularly in macrophages and partially adipocytes, suggesting these G-protein-coupled receptors as pharmacological targets on the ongoing innovative drugs, which seem cardiometabolically healthy well beyond their effects on glucose and body weight.

Human epicardial adipose tissue (EAT) is a unique and multifunctional fat compartment of the heart. Microscopically, EAT is composed of adipocytes, nerve tissues, inflammatory, stromovascular, and immune cells. Epicardial adipose tissue is a white adipose tissue, albeit it also has brown fat-like or beige fat-like features. No muscle fascia divides EAT and myocardium; this allows a direct interaction and crosstalk between the epicardial fat and the myocardium. Due to its distinctive transcriptome and functional proximity to the heart, EAT can play a key role in the development and progression of coronary artery disease, atrial fibrillation, and heart failure. Clinically, EAT, given its rapid metabolism and simple measurability, can be considered a novel therapeutic target, owing to its responsiveness to drugs with pleiotropic and clear beneficial cardiovascular effects such as the glucagon-like peptide-1 receptor (GLP-1R) agonists.Human EAT is found to express the genes encoding the receptors of glucose-dependent insulinotropic polypeptide receptor (GIPR), glucagon receptor (GCGR), and GLP-1. The immunohistochemistry indicates that GIP and GCG receptor proteins are present in EAT samples. Epicardial adipose tissue GIPR is inversely associated with genes involved in free fatty acid (FFA) oxidation and transport and with genes promoting FFA biosynthesis and adipogenesis. Epicardial adipose tissue GCGR is correlated with genes promoting FFA transport and activation for mitochondrial beta-oxidation and white-to-brown adipocyte differentiation and with genes reducing FFA biosynthesis and adipogenesis.As the myocardium relies mostly on FFAs as fuel and is in direct contiguity with EAT, these findings may have a great importance for the modulation of the myocardial activity and performance. Given the emerging use and cardiovascular effects of GLP-1R agonists, dual GIPR/GLP-1R agonists, and GLP-1R/GIPR/GCGR triagonists, we believe that pharmacologically targeting and potentially modulating organ-specific fat depots through G-protein­coupled receptors may produce beneficial cardiovascular and metabolic effects.

BNT162b2 Booster Dose Elicits a Robust Antibody Response in Subjects with Abdominal Obesity and Previous SARS-CoV-2 Infection.

Little is known about the long-term durability of the induced immune response in subjects with obesity, particularly in those with an abdominal distribution of adipose tissue. We evaluated SARS-CoV-2-specific antibody responses after BNT162b2 vaccine booster dose, comparing individuals with and without abdominal obesity (AO), discerning between individuals previously infected or not. IgG-TrimericS were measured in 511 subjects at baseline, on the 21st day after vaccine dose 1, and at 1, 3, 6, and 9 months from dose 2, and at 1 and 3 months following the booster dose. To detect SARS-CoV-2 infection, nucleocapsid antibodies were measured at baseline and at the end of the study. Multivariable linear regression evaluated the three-month difference in the absolute variation in IgG-TrimericS levels from booster dose, showing AO and SARS-CoV-2 infection status interactions (p = 0.016). Regardless of possible confounding factors and IgG-TrimericS levels at the booster dose, AO is associated with a higher absolute change in IgG-TrimericS in prior infected individuals (p = 0.0125). In the same regression model, no interaction is highlighted using BMI (p = 0.418). The robust response in the development of antibodies after booster dose, observed in people with AO and previous infection, may support the recommendations to administer a booster dose in this population group.

Rationale and design of the CV-PREVITAL study: an Italian multiple cohort randomised controlled trial investigating innovative digital strategies in primary cardiovascular prevention.

INTRODUCTION: Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking. METHODS AND ANALYSIS: The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners' offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed. ETHICS AND DISSEMINATION: This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study's course and findings through regular meetings. TRIAL REGISTRATION NUMBER: NCT05339841.

Osteomyelitis, Oxidative Stress and Related Biomarkers.

Bone is a very dynamic tissue, subject to continuous renewal to maintain homeostasis through bone remodeling, a process promoted by two cell types: osteoblasts, of mesenchymal derivation, are responsible for the deposition of new material, and osteoclasts, which are hematopoietic cells, responsible for bone resorption. Osteomyelitis (OM) is an invasive infectious process, with several etiological agents, the most common being Staphylococcus aureus, affecting bone or bone marrow, and severely impairing bone homeostasis, resulting in osteolysis. One of the characteristic features of OM is a strong state of oxidative stress (OS) with severe consequences on the delicate balance between osteoblastogenesis and osteoclastogenesis. Here we describe this, analyzing the effects of OS in bone remodeling and discussing the need for new, easy-to-measure and widely available OS biomarkers that will provide valid support in the management of the disease.