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Context Vitamin D (Vit-D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) are the major calciotropic hormones involved in the regulation of blood calcium levels from the intestine, kidney, and bone through a tight endocrine feedback loop system. Altered levels of calcium itself or through the effect of its regulatory hormones could affect blood pressure (BP), but the exact mechanisms remain unclear. Objective To evaluate whether a causal relationship exists between serum calcium level and/or the regulatory hormones involved in its homeostasis with BP, we performed a two-sample Mendelian randomization (MR) study. Methods From 4 large genome-wide association studies (GWAS) we obtained independent (r2 < 0.001) single nucleotide polymorphisms (SNPs) associated with serum calcium (119 SNPs), Vit-D (78 SNPs), PTH (5 SNPs), and FGF23 (5 SNPs), to investigate through MR their association with systolic BP (SBP) and diastolic BP (DBP) in a Swedish urban-based study, the Malmö Diet and Cancer study (n = 29 298). Causality was evaluated by the inverse variance weighted method (IVW) and weighted median, while MR Egger and MR-PRESSO were used as sensitivity analyses. Results Genetically predicted serum calcium level was found to be associated with DBP (IVW: beta = 0.10, SE = 0.04, P = 0.007) and SBP (IVW: beta = 0.07, SE = 0.04, P = 0.04). Genetically predicted Vit-D and PTH showed no association with the traits, while FGF23 was inversely associated with SBP (IVW: beta = −0.11, SE = 0.04, P = 0.01), although this association lost statistical significance in sensitivity analysis. Conclusion Our study shows a direct association between genetically predicted calcium level and DBP, and a weaker association with SBP. No such clear association was found for genetically predicted calciotropic hormone levels. It is of interest to detect which target genes involved in calcium homeostasis mediate the effect of calcium on BP, particularly for improving personalized intervention strategies.

Evidence of the involvement of the cardiovascular system in patients with COVID-19 is increasing. The evaluation of the subclinical cardiac involvement is crucial for risk stratification at admission, and left ventricular global longitudinal strain (LVGLS) may be useful for this purpose. A total of 87 consecutive patients admitted to the COVID Center were enrolled from December 2020 to April 2021. A complete echocardiography examination was performed within 72 hours from admission. The main outcome was the need for mechanical ventilation by way of orotracheal intubation (OTI) and mortality, and the secondary outcome was the worsening of the respiratory function during hospitalization, interpreted as a decrease of the ratio between the partial pressure of oxygen and the fraction of inspired oxygen (P/F)

Introduction To better define COVID-19 long-term impact we prospectively analysed patient-centred outcomes, including general health and symptom duration. Methods Barthel index (BI), St. George’s Respiratory Questionnaire adapted to patients with COVID-19 (aSGRQ) and WHO Clinical Progression Scale (CPS) were measured at enrolment and at 6 weeks from the onset of symptoms. Persistence of most frequently reported symptoms was assessed at 6 weeks and, among symptomatic patients, at 12 weeks from the onset of symptoms. Predictors of impaired general health over time were identified using an ordinal multilevel multivariate model. Results A total of 448 patients (55% men, median age 56 years) were enrolled. WHO-CPS showed mild, moderate and severe disease in 48%, 42% and 10% of patients at admission and mild disease in all patients at follow-up, respectively. BI and aSGRQ were normal in 96% and 93% patients before COVID-19 but only in 47% and 16% at COVID-19 diagnosis and in 87% and 65% at 6-week follow-up. Male gender was identified by all three assessments as a predictor of impaired general health (BI, OR 2.14, p

Antibiotic stewardship (AS) is a cornerstone of the fight against antimicrobial resistance; however, evidence on the best practice to improve antibiotic prescription in various hospital settings is still scarce. This study aimed to measure the efficacy of a non-restrictive AS intervention in the internal medicine area of a tertiary-care hospital across a 3-year period.The intervention comprised a 3-month 'intensive phase' based on education and guidelines provision, followed by 9 months of audits and feedback activities. The primary outcome was the overall antibiotic consumption measured as days of therapy (DOTs) and defined daily doses (DDDs). Secondary outcomes were carbapenem and fluoroquinolone consumption, all-cause in-hospital mortality, length of stay, incidence of Clostridioides difficile and carbapenem-resistant Enterobacterales bloodstream infections (CRE-BSIs). All outcomes were measured in the intervention wards comparing the pre-phase with the post-phase using an interrupted time-series model.A total of 145 337 patient days (PDs) and 14 159 admissions were included in the analysis. The intervention was associated with reduced DOTs*1000PDs (-162.2/P = 0.005) and DDDs*1000PDs (-183.6/P ≤ 0.001). A sustained decrease in ward-related antibiotic consumption was also detected during the post-intervention phase and in the carbapenem/fluoroquinolone classes. The intervention was associated with an immediate reduction in length of stay (-1.72 days/P0.001) and all-cause mortality (-3.71 deaths*100 admissions/P = 0.002), with a decreasing trend over time. Rates of Clostridioides difficile infections and CRE-BSIs were not significantly impacted by the intervention.The AS intervention was effective and safe in decreasing antibiotic consumption and length of stay in the internal medicine area. Enabling prescribers to judicious use of antimicrobials through active participation in AS initiatives is key to reach sustained results over time.

Cardiovascular (CV) diseases are burdened by high mortality and morbidity, being responsible for half of the deaths in Europe. Although hypertension is recognized as the most important CV risk factor, hypertension awareness, and blood pressure (BP) control are still unsatisfactory. In 2017 and 2018, respectively >10 000 and >5000 individuals took part in the May Measurement Month (MMM) campaign in Italy, of whom 30.6% and 26.3% were found to have high BP, respectively. To raise public awareness on the importance of hypertension and to collect BP data on a nation-wide scale in Italy. In the frame of the MMM campaign, an opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2019. BP measurement, the definition of hypertension, and statistical analysis followed the standard MMM protocol. Screening was conducted in multiple sites by health personnel. Among the 10 182 people screened (females: 52.3%, mean age 58 ± 16years) mean BP was 127/78 mmHg, and 3171 (31.1%) participants had arterial hypertension, of whom 62.1% were aware of being hypertensive. Diabetes, body mass index >25 kg/m2 were associated with higher BP and previous myocardial infarction with lower BP. For the third consecutive year we collected a nation-wide snapshot of BP control in a large sample of individuals. The high participation, with some yearly fluctuations likely due to the limitations of the sampling technique, confirms the power of this kind of health campaign in reaching a significant number of people to raise awareness on health topics.

Hepatitis C virus (HCV)-related chronic infection has been associated with a higher incidence of cardiovascular diseases. An altered morphology and function of both left and right heart have been described in HCV patients; however, the causality of the association is still debated. Ninety-eight nonobese and nondiabetic HCV patients (59.5 ± 12.0 years; males 52%) with Fibroscan-Transient Elastography assessed low-moderate liver fibrosis that achieved sustained viral response at 12 and 24 weeks after DAAs (direct-acting antivirals) participated. 56 were matched with 52 control subjects for age, sex and cardiovascular risk factors at baseline. A trans-thoracic echocardiography was performed in each subject at baseline (T0) and repeated in all HCV patients after eradication (6 months later eligibility, T1). TNF-α and IL-10 were measured at baseline and at T1. A concentric remodelling of the left heart in HCV participants was identified, whereas tricuspidal annular plane systolic excursion, right indexed atrial volume, right basal ventricular diameter, inferior vena cava diameter and pulmonary arterial pressure were higher in HCV participants compared to matched controls. After virus eradication, left indexed atrial volume and all right cardiac chambers measures were lower than baseline. A significant reduction of TNF-α was shown at T1, while IL-10 did not change. This study shows a concentric remodelling of the left ventricle and structural modifications in the right sections in HCV patients compared to controls. Virus eradication with DAAs was associated with a reduction of the main right atrioventricular parameters indicating a direct involvement of the HCV in cardiac changes.

Patients with rheumatoid arthritis (RA) have an increased incidence of cardiovascular events. Ultrasound examination of the carotid arteries can show the presence of plaques and detect the atherosclerotic subclinical process through the evaluation of intima-media thickness (cIMT) and carotid segmental distensibility (cCD). The aim of the present study was to identify which factors could independently influence the evolution of atherosclerosis (plaques, cIMT, and cCD) after 1 year of follow-up in a sample of patients with RA. A total of 137 patients with RA without previous cardiovascular (CV) events were enrolled at baseline, and 105 (M/F: 21/84, age 59.34 ± 11.65 years) were reassessed after one year using ultrasound of carotid arteries to detect atheromatous plaques and to measure cIMT and cCD. After one year, all the indices of subclinical atherosclerosis worsened with respect to baseline (Δ-cIMT = 0.030 ± 0.10 mm, p = 0.005; Δ-cCD = -1.64 ± 4.83, 10-3/KPa, p = 0.005; Δ-plaques = 8.6%, p = 0.035). Traditional CV risk factors (age, mean arterial pressure, and diabetes) and corticosteroid therapy were independently associated with the worsening of subclinical atherosclerosis. Interestingly, when considering RA patients divided according to the degree of disease activity score 28 with C-reactive protein (DAS28 [CRP] ≥2.6), the worsening of subclinical atherosclerosis indices was detectable exclusively in the group of patients with active disease. Our longitudinal study supports the hypothesis of a key role of both traditional CV risk factors and the inflammatory activity of arthritic disease in the progression of subclinical atherosclerosis in RA patients. In addition, corticosteroids might have a deleterious effect.

Current literature suggests a higher risk of pregnancy-related complications in patients with renal fibromuscular dysplasia (FMD). The aim of our study was to assess the nature and prevalence of pregnancy-related complications in patients subsequently diagnosed with FMD. A call for participation was sent to centers contributing to the European/International FMD Registry. Patients with at least 1 pregnancy were included. Data on pregnancy were collected through medical files and FMD characteristics through the European/International FMD Registry. Data from 534 pregnancies were obtained in 237 patients. Despite the fact that, in 96% of cases, FMD was not diagnosed before pregnancy, 40% of women (n=93) experienced pregnancy-related complications, mostly gestational hypertension (25%) and preterm birth (20%), while preeclampsia was reported in only 7.5%. Only 1 patient experienced arterial dissection and another patient an aneurysm rupture. When compared with patients without pregnancy-related complications, patients with complicated pregnancies were younger at FMD diagnosis (43 versus 51 years old; P P =0.003) but underwent more often renal revascularization (63% versus 40%, P

Aging with multimorbidity and polytherapy are the most significant factors that could led to inappropriate prescribing of contraindicated medications in patients with chronic kidney disease (CKD). The aim of this study was to evaluate the prescriptions of contraindicated drugs in older adults in CKD and to identify their associated factors in a hospital context. An observational retrospective study was carried out considering all patients ≥65 years with at least one serum creatinine value recorded into the REPOSI register into 2010–2016 period. The estimated glomerular filtration rate (eGFR) was applied to identify CKD. A descriptive analysis was performed to compare demographic and clinical characteristics; logistic regression models were used to estimate factors of inappropriate and percentage changes of drug use during hospitalization. A total of 4,713 hospitalized patients were recorded, of which 49.8% had an eGFR 2; the 21.9% were in treatment with at least one inappropriate drug at the time of hospital admission with a decrease of 3.0% at discharge (p = 0.010). The probability of using at least one contraindicated drug was significantly higher in patients treated with more several drugs (OR 1.21, 95% CI 1.16–1.25, p p < 0.001; G5: 19.38, 11.51–32.64, p < 0.001). Low-dose acetylsalicylic acid was the contraindicated drug mainly used at the time of admission, reducing 1.2% at discharge. An overall increase in therapeutic appropriateness in hospitalized older patients with CKD was observed, despite a small percentage of therapeutic inappropriateness at discharge that underlines the need for a closer collaboration with the pharmacologist to improve the drug management.

Polyfluoro- and perfluoro–alkyl substances (PFAS) are organic chemicals extensively used worldwide for industry and consumer products. Due to their chemical stability, PFAS represent a major cause of environmental pollution. PFAS accumulate in animal and human blood and tissues exerting their toxicity. We performed a review of the epidemiological studies exploring the relationship between exposure to PFAS and thromboembolic cardiovascular disease. An increase in cardiovascular disease or death related to PFAS exposure has been reported from cross-sectional and longitudinal observational studies with evidence concerning the relation with early vascular lesions and atherosclerosis. Several studies indicate an alteration in lipid and glucose metabolism disorders and increased blood pressure as a possible link with cardiovascular thromboembolic events. We also examined the recent evidence indicating that legacy and new PFAS can be incorporated in platelet cell membranes giving a solid rationale to the observed increase risk of cardiovascular events in the populations exposed to PFAS by directly promoting thrombus formation. Exposure to PFAS has been related to altered plasma membrane fluidity and associated with altered calcium signal and increased platelet response to agonists, both in vitro and ex vivo in subjects exposed to PFAS. All the functional responses are increased in platelets by incorporation of PFAS: adhesion, aggregation, microvesicles release and experimental thrombus formation. These findings offer mechanistic support the hypothesis that platelet-centred mechanisms may be implicated in the increase in cardiovascular events observed in populations chronically exposed to PFAS.

Opportunistic screening of atrial fibrillation is a valuable approach to the identification of subjects with unknown or non-symptomatic atrial fibrillation (AF) with the potential of reducing the burden of ischemic stroke in the population. To evaluate the feasibility of a large-scale screening for atrial fibrillation using a blood pressure monitor (MicrolifeAFIB) endowed with a validated algorithm able to detect AF calculating the irregularity of interval times between heartbeats. In this cross-sectional study conducted in 74 pharmacies in Verona participated 3071 people aged 50 years or more. In 6 months, information about drugs, previous diagnoses of cardiovascular diseases, anthropometric and demographic data was recorded, together with the measurement of blood pressure and cardiac rhythm by using the MicrolifeAFIB device. Pharmacists also collected anthropometric and demographic data of the participants, along with information concerning their personal history of cardiovascular disease and the use of antihypertensive and antithrombotic agents. All those who were positive at the screening for atrial fibrillation were referred to their family doctor. The screening revealed 98 subjects (3.2%) positive for AF; 44 of these reported a previous diagnosis of AF and were treated with anticoagulants (77%) or with antiplatelet agents (7%). By logistic regression analysis, age, male sex and heart failure were independently associated with positivity for AF. Association between positive test and previous stroke/TIA was found in the 54 subjects without a previous diagnosis of AF (9% had a previous stroke/TIA). Opportunistic screening for atrial fibrillation in the pharmacies is feasible and allows to identify a number of subjects with silent, non-previously diagnosed AF, therefore is potentially useful in large-scale projects aimed at the prevention of cardiovascular morbidity and mortality.

A genetic risk score (GRS) based on 29 single nucleotide polymorpysms (SNPs) associated with high blood pressure (BP) was prospectively associated with development of hypertension, stroke and cardiovascular events. The aim of the present study was to evaluate the impact of this GRS on the incidence of aortic disease, including aortic dissection (AD), rupture or surgery of a thoracic (TAA) or abdominal (AAA) aortic aneurysm. More than 25,000 people from the Swedish Malmo Diet and Cancer Study had information on at least 24 SNPs and were followed up for a median ≥ 18 years. The number of BP elevating alleles of each SNPs, weighted by their effect size in the discovery studies, was summed into a BP-GRS. In Cox regression models, adjusted for traditional cardiovascular risk factors including hypertension, we found significant associations of the BP-GRS, prospectively, with incident TAA (hazard ratio (HR) 1.64 (95% confidence interval (CI) 1.081-2.475 comparing the third vs. the first tertile; p = 0.020) but not with either AAA or aortic dissection. Calibration, discrimination and reclassification analyses show modest improvement in prediction using the BP-GRS in addition to the model which used only traditional risk factors. A GRS for hypertension associates with TAA suggesting a link between genetic determinants of BP and aortic disease. The effect size is small but the addition of more SNPs to the GRS might improve its discriminatory capability.

Ion channels are transmembrane proteins that play important roles in cell function regulation modulating ionic cell permeability. In megakaryocytes and platelets, regulated ion flows have been demonstrated to modulate platelet production and function. However, a relatively limited characterization of ion channel expression and function is available in the human megakaryocyte-platelet lineage.We analyzed the expression and function of the large-conductance calcium and voltage-activated potassium channel KTo investigate the functionality of KIn megakaryocytes, KThe present study reveals new mechanisms in platelet formation and activation, suggesting that targeting K

Objective: to compare COVID-19 patients’ vessel caliber with that of normal lungs and lungs interested by other inflammatory and thromboembolic processes. Methods: between March and April 2020, 42 patients affected by COVID-19 pneumonia [COV-P] underwent a CT scan of the lung at Verona University Hospital for clinical indications. Lung images were compared to 4 different groups of patients (normal lung [NL], distal thromboembolism [DTE], bacterial and fungal pneumonia [Bact-P, Fung-P]) by a 4-year-experienced radiologist. Results: COV-P patients’ segmental and subsegmental vessels, as evaluated as the ratio with the corresponding bronchial branch (V/B ratio) were larger with respect to NL, DTE in the apparently healthy parenchyma, a result confirmed in the zones of opacification with respect to Bact-P and Fung-P. Conclusions: This is the first study to comparatively showing that segmental and subsegmental COVID-19 patients’ vessel caliber is significantly enlarged. This is a distinctive feature of COVID-19 pneumonia suggesting distinct pathophysiology as compared to other inflammatory and thromboembolic diseases and alerting radiologists to consider it when evaluating CT scan of suspected patients.

Background: Sacubitril/valsartan, the first agent to be approved in a new class of drugs called angiotensin receptor neprilysin inhibitors (ARNIs), has been shown to reduce cardiovascular mortality and morbidity compared to enalapril in outpatient subjects with chronic heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, there is little real-world evidence about the efficacy of ARNIs in elderly hypertensive patients with HFrEF and comorbidities. Methods: In this prospective open-label study, 108 subjects, 54 of them (mean age 78.6 ± 8.2 years, 75.0 % male), with HFrEF (29.8 ± 4.3 %) and New York Heart Association (NYHA) class II-III symptoms were assigned to receive ARNIs twice daily, according to the recommended dosage of 24/26, 49/51, 97/103 mg. Patients were gender- and age-matched with a control arm of patients with HFrEF receiving the optimal standard therapy for HF. The clinic blood pressure (BP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR), blood glucose and glycated hemoglobin (HbA1c), uric acid (UA), left ventricular ejection fraction (LVEF) and NYHA class were evaluated at a mean follow-up of 12 months. During the follow-up, the clinical outcomes, including mortality and re-hospitalization for HF, were collected. Results: NYHA class significantly improved in the ARNI arm compared to the control (24.9 vs. 6.4 %, shifting from class III to II, and 55.4 vs. 25.2 %, from class II to I, p

We studied the influence of cardiovascular (CV) risk factors, previous CV events, and cotreatments with preventive medicines, on residual platelet thromboxane (TX)B2 production in 182 patients chronically treated with enteric coated (EC)-aspirin (100 mg/day). The response to aspirin was also verified by assessing arachidonic acid-induced platelet aggregation and urinary 11-dehydro-TXB2 levels. Residual serum TXB2 levels exceeded the upper limit value for an adequate aspirin response in 14% of individuals. This phenomenon was detected at 12 hours after dosing with aspirin. The coadministration of statins (mostly atorvastatin) was an independent predictor of residual serum TXB2 levels, and the percentage of patients with enhanced values was significantly lower in statin users vs. nonusers. We provide evidence in vitro that atorvastatin reduced residual TXB2 generation by increasing the extent of acetylation of platelet COX-1 by aspirin. In conclusion, the coadministration of statins may counter the mechanisms associated with reduced bioavailability of aspirin detected in some individuals with CV disease.

Obesity leads to the clustering of cardiovascular (CV) risk factors and the metabolic syndrome (MetS) also in children and is often accompanied by non-alcoholic fatty liver disease. Quality of dietary fat, beyond the quantity, can influence CV risk profile and, in particular, omega-3 fatty acids (FA) have been proposed as beneficial in this setting. The aim of the study was to evaluate the associations of individual CV risk factors, characterizing the MetS, with erythrocyte membrane FA, markers of average intake, in a group of 70 overweight/obese children. We conducted an observational study. Erythrocyte membrane FA were measured by gas chromatography. Spearman correlation coefficients (rS) were calculated to evaluate associations between FA and features of the MetS. Mean content of Omega-3 FA was low (Omega-3 Index = 4.7 ± 0.8%). Not omega-3 FA but some omega-6 FA, especially arachidonic acid (AA), were inversely associated with several features of the MetS: AA resulted inversely correlated with waist circumference (rS = − 0.352), triglycerides (rS = − 0.379), fasting insulin (rS = − 0.337) and 24-h SBP (rS = − 0.313). Total amount of saturated FA (SFA) and specifically palmitic acid, correlated positively with waist circumference (rS = 0.354), triglycerides (rS = 0.400) and fasting insulin (rS = 0.287). Fatty Liver Index (FLI), a predictive score of steatosis based on GGT, triglycerides and anthropometric indexes, was positively correlated to palmitic acid (rS = 0.515) and inversely to AA (rS = − 0.472). Our data suggest that omega-6 FA, and especially AA, could be protective toward CV risk factors featuring the MetS and also to indexes of hepatic steatosis in obese children, whereas SFA seems to exert opposite effects.

Lycopene is a carotenoid found in tomatoes previously shown bioactive in endothelial cells. We studied in vitro cell migration, key step in angiogenesis using the scratch wound healing assay to test the effects of lycopene (2 µmol/L) on Human Umbilical Vein Endothelial Cells. To explore the cellular mechanism, we measured nitric oxide (NO) release and protein kinase B (Akt) phosphorylation. Lycopene inhibited cell migration induced by vascular endothelial growth factor-A (VEGFA) and reduced Akt phosphorylation. NO generation in endothelial cells, assessed by using difluorofluorescein diacetate, was increased by lycopene alone or in combination with VEGFA and blunted by NO synthase inhibition. Increased nitrite-nitrate concentration in culture medium indicates effects of lycopene on NO bioavailability, potentially implicated in the reduction in VEGFA-induced cell migration, as observed with a NO-donor. In conclusion, lycopene inhibits endothelial cells migration modulating VEGFA signalling system. Increased NO generation partly explains lycopene bioactivity.

Patients with chronic inflammatory arthritis experience an increased incidence of cardiovascular (CV) events. In addition to visualizing atherosclerotic plaques, ultrasound examinations (USs) of the carotid arteries permit the measurement of subclinical markers of atherosclerosis, such as intima-media thickness (cIMT) and carotid segmental distensibility (cDC). The aims of the study were to identify the determinants of atherosclerosis acceleration (plaques, cIMT and cDC) in a sample of patients suffering from chronic arthritis and to compare these patients with a control group of people with ≤1 traditional risk factor (TRF) for CV disease.We recruited 137 patients with rheumatoid arthritis (RA), 43 patients with psoriatic arthritis (PsA), 28 patients with ankylosing spondylitis (AS) and 48 healthy volunteers without histories of previous CV events. These patients underwent carotid artery US examinations using dedicated hardware.Regression and multivariate analyses demonstrated that only age (p0.001) was consistently associated with cDC, cIMT and atherosclerotic plaques, both in the entire sample of patients with arthritis and in the subgroup of patients with RA. Among modifiable TRFs for cardiovascular disease, only hypertension, diabetes mellitus and smoking exhibited associations with some carotid phenotypes, with borderline significance. When patients with RA carrying ≤1 TRF were compared with control subjects carrying ≤1 TRF, only cDC was slightly lower in the RA group than in the control group.Age is the major determinant of subclinical atherosclerosis in patients with different types of arthritis, as the contributions of other TRFs and disease activity and duration indices to the disease seem to be limited.

The cystine-knot miniproteins present in tomato fruit (TCMPs) have been shown to exert anti-angiogenic effects by inhibiting endothelial cell migration and to display resistance to gastrointestinal proteolytic attack. To better define the pharmacological potential of TCMPs, their oral bioavailability and their resistance to industrial processing must be assessed. To explore the intestinal transport of TCMPs we used the differentiated Caco-2 cells model. After 24 h incubation, 37.73 ± 9.34% of TCMPs crossed the epithelium, without altering the integrity of the cell layer. To assess the effects of the industrial processing on the biochemical features and the biological activity of TCMPs, we developed a method for purifying the proteins from tomato paste. The tomato-paste purified TCMPs retained the resistance to gastrointestinal digestion and the inhibitory activity towards endothelial cell migration. Our previous and present results collectively demonstrate that TCMPs possess interesting features for drug development.

Treatment of obstructive sleep apnoea (OSA) has been shown to reduce blood pressure (BP). However, the effect size is modest and treatment of OSA is not recommended as the only treatment target when treating hypertension. The aim of this systematic review and meta-analysis was to identify potential predictors for BP response in patients with OSA undergoing CPAP treatment. A systematic search was conducted in three databases (MEDLINE, Embase and Web of Science) between January 1st 1960 to December 31st 2017 using terms exploring three domains (obstructive sleep apnoea, CPAP, clinical trial) Out of 2445 articles, 59 RCTs were included (n=7,329 subjects) comparing CPAP with control groups. CPAP was associated with a net reduction in systolic BP of -2.12 (95% CI -2.82 to -1.42) mmHg and in diastolic BP of -1.97 (95% CI -2.46 to -1.48) mmHg, favouring treatment of OSA using CPAP (both p-values Younger patients (

Depression is often under-recognized in older patients, even if antidepressants (AD) are commonly prescribed, with a prevalence of use that increase with ageing [ 1 ]. Nevertheless, even if a diagnosis of depression is established, inappropriate treatment can occur [ 2 ]. Beers criteria are the most widely screening tools used to detect inappropriate prescription of drugs in people aged 65 years or more [ 3 ]. Since 2010, attempts to adapt the Beers' criteria have been made in Europe [ 4 , 5 ]. Tricyclic drugs are the ADs to be always avoided in the elderly, owing to their anticholinergic side effects, such as cognitive impairment, delirium, urinary retention and falls [ 3 ]. Selective serotonin reuptake inhibitors (SSRIs) should be used with caution because they can cause or exacerbate hyponatraemia [ 3 ]. To our knowledge no studies have been conducted on recent data collected in hospitalized older patients in order to assess the appropriateness of prescription of ADs. With this background, the objectives of this study were to investigate the prevalence of AD use and prescription appropriateness, according to the above-cited criteria, in a large cohort of older patients hospitalized in Italian internal medicine and geriatric wards from 2010 to 2017.

The aims of this study were to assess the prevalence of use and prescription appropriateness of drugs for peptic ulcer and gastrooesophageal reflux disease (GERD) at hospital admission and discharge. Patients aged 65 years or more hospitalized from 2010 to 2016 in 101 Italian internal medicine and geriatric wards in the context of the REPOSI register were scrutinized to assess if they were prescribed with drugs for peptic ulcer and GERD at hospital admission and discharge. Appropriateness of prescription was assessed considering the presence of specific conditions (i.e., history of peptic ulcer or gastrointestinal hemorrhages, advanced age, Helicobacter Pylori) or gastro-toxic drug combinations, according to the criteria provided by the reimbursement rules of the Agenzia Italiana del Farmaco (NOTA 1 and 48). Among 4715 enrolled patients, 3899 were discharged alive. At hospital discharge, 2412 (61.9%, 95%CI: 60.3–63.4%) patients were prescribed with drugs for peptic ulcer and GERD, a 12% of increase from hospital admission. Almost half of the patients (N = 1776, 45.6%, 95%CI: 44.0–47.1%) were inappropriately prescribed or not prescribed: among the drugs for peptic ulcer and GERD users, about 60% (1444/2412) were overprescribed, and among nonusers, 22% (332/1487) were underprescribed. Among patients newly prescribed at hospital discharge, 60% (392/668) were inappropriately prescribed. The appropriateness of drugs for peptic ulcer and GERD therapy decreased by 3% from hospital admission to discharge. Hospitalization missed the opportunity to improve the quality of prescription of this class of drug.

Syncope is a temporary loss of consciousness due to transient global cerebral hypoperfusion. Reflex syncope is the most frequent, representing 21% of all types of syncopal events, and includes: (a) the vasovagal syncope (classical type); (b) the situational syncope; (c) the carotid sinus syncope and (d) non-classical forms. An accurate anamnesis and physical examination are fundamental for the diagnosis. Although limited evidence is available regarding the efficacy of some treatments, a number of these can be successfully used in the clinical practice. It is, however, important to personalize the therapeutic approach in order to achieve an efficient reduction or suppression of syncopal episodes. Patients should be reassured about the benignity of these events and the possibility of reducing their frequency over time. They should be also educated on how to recognize and abort incoming syncopal episodes. Patients may be advised to increase their introit in water and salt, as well as to reduce vasoactive medications, if no contraindications exist. Orthostatic training may be beneficial but only in very motivated young patients capable of strictly adhering to the exercise plan. So far, any proposed pharmacological treatment has demonstrated very limited efficacy and, therefore, it should be tried in case of failure of non-pharmacological approaches. Pacemaker implantation is clearly indicated in patients with documented cardioinhibitory syncope in the absence of a vasodepressor component, which can compromise their quality of life. Despite the American and European guidelines for the treatment of syncope are similar, still some differences can be denoted. Aim of this study is to evaluate the management of patients with recurrent syncopal episodes focusing on pharmacological and non-pharmacological approaches.

Cystine-knot miniproteins are a class of 30-50 amino acid long peptides widespread in eukaryotic organisms. Due to their very peculiar three-dimensional structure, they exhibit high resistance to heat and peptidase attack. The cystine-knot peptides are well represented in several plant species including medicinal herbs and crops. The pharmacological interest in plant cystine-knot peptides derives from their broad biological activities, mainly cytotoxic, antimicrobial and peptidase inhibitory and in the possibility to engineer them to incorporate pharmacophoric information for oral delivery or disease biomonitoring. The mechanisms of action of plant cystine-knot peptides are still largely unknown, although the capacity to interfere with plasma membranes seems a feature common to several cystine-knot peptides. In some cases, such as potato carboxypetidase inhibitor (PCI) and tomato cystine-knot miniproteins (TCMPs), the cystine-knot peptides target human growth factor receptors either by acting as growth factor antagonist or by altering their signal transduction pathway. The possibility to identify specific molecular targets of plant cystine-knot peptides in human cells opens novel possibilities for the pharmacological use of these peptides besides their use as scaffold to develop stable disease molecular markers and therapeutic agents.

Essentials The reliability of platelet tests as markers of the variable bioavailability of clopidogrel is not yet defined. Kinetics of clopidogrel active metabolite (CAM) and platelet response were studied in ischemic heart disease. CAM plasma maximum concentration (Cmax) predicted vasodilator-stimulated phosphoprotein (VASP-P). Timely performed VASP-P, not an aggregation-based test, may be a surrogate for clopidogrel bioavailability. SummaryBackground The high inter-individual variability in the inhibition of platelet function by clopidogrel is mostly explained by high variability in its transformation to an active metabolite (CAM). Objective We investigated the relations between pharmacokinetics and pharmacodynamics of CAM by comparing two methods of platelet function. Methods We enrolled 14 patients undergoing percutaneous coronary interventions for non-ST-segment elevation acute coronary syndrome or inducible myocardial ischemia. Plasma concentrations of clopidogrel and CAM, phosphorylation of vasodilator-stimulated phosphoprotein (VASP-P), expressed as a platelet reactivity index (PRI) and whole-blood platelet aggregation (multiple electrode aggregometer, MEA) were measured before and after a 600-mg clopidogrel loading dose (nine time-points) and before and after 75-mg maintenance doses on days 2, 7 and 30. Results Plasma concentrations of clopidogrel and CAM were highly variable. CAM reached maximal concentration (Cmax) (median, 110.8 nm; range, 41.9–484.8) 0.5–2 h after the loading dose. A sigmoid dose‒response curve defined the relations between CAMCmax and PRI after 3 to 24 h (IC50, 459.6 nm; 95% confidence interval, 453.4–465.7; R2 = 0.82). PRI was unchanged from baseline in patients with the lowest CAMCmax (< 83 nm, n = 7), indicating low sensitivity of VASP-P. PRI values were also predicted by CAMCmax at days 2, 7 and 30. Platelet aggregation measured by MEA did not show significant relations with either PRI or with CAM pharmacokinetics at any time-point. Conclusions After 600 mg clopidogrel, VASP-P, but not whole-blood platelet aggregation measured by MEA, is almost entirely predicted by CAMCmax. VASP-P could be useful in studies aimed at investigating relations between CAM bioavailability and clinical events.

In previous studies, dietary and circulating fatty acids (FA) and desaturases activity (delta-5 desaturase [D5D], delta-6 desaturase [D6D], and stearoyl-CoA desaturase [SCD-16]) involved in their metabolism were associated with metabolic and cardiovascular disorders. The aim of the study was to assess the association between different FAs and desaturases activity (estimated as product:precursor ratios) with individual cardiovascular risk factors (in particular, anthropometric measurements and blood pressure [BP]) in children. The FA profile was determined on a whole-blood drop in 243 children (age: 8.6 &plusmn, 0.72 years) participating in a school-based cross-sectional study. Docosahexaenoic acid (DHA) inversely correlated with indices of adiposity, glucose, and triglycerides. Palmitoleic acid and SCD-16 were directly associated with markers of adiposity and BP, even after adjustment for main confounders. D6D correlated directly with the waist/height ratio. Children with excess weight (&gt, 85th percentile, that is overweight plus obese ones) showed higher palmitic acid, palmitoleic acid, and higher SCD-16 activity as compared to normal-weight children. Most of the associations were confirmed in the excess-weight group. Omega-3 FAs, particularly DHA, but not omega-6 FA, showed a potentially beneficial association with metabolic parameters, whereas palmitoleic acid and SCD-16 showed a potentially harmful association with indices of adiposity and BP, especially in obese children.

The thromboxane (TX) A2 elicits TP-dependent different platelet responses. Low amounts activate Src kinases and the Rho–Rho kinase pathway independently of integrin αIIbβ3 and ADP secretion and synergize with epinephrine to induce aggregation. Aim of the present study was to investigate the role Src kinases and the interplay with calcium signals in reactive oxygen species (ROS) generation in the activatory pathways engaged by TXA2 in human platelets. All the experiments were performed in vitro or ex vivo. Washed platelets were stimulated with 50–1000 nM U46619 and/or 10 μM epinephrine in the presence of acetylsalicylic acid and the ADP scavenger apyrase. The effects of the ROS scavenger EUK-134, NADPH oxidase (NOX) inhibitor apocynin, Src kinase inhibitor PP2 and calcium chelator BAPTA were tested. Intracellular calcium and ROS generation were measured. Platelet rich plasma from patients treated with dasatinib was used to confirm the data obtained in vitro. We observed that 50 nM U46619 plus epinephrine increase intracellular calcium similarly to 1000 nM U46619. ROS generation was blunted by the NOX inhibitor apocynin. BAPTA inhibited ROS generation in resting and activated platelets. Phosphorylation of Src and MLC proteins were not significantly affected by antioxidants agents. BAPTA and antioxidants reduced P-Selectin expression, activation of integrin αIIbβ3and platelet aggregation. TXA2-induced increase in intracellular calcium is required for Src phosphorylation and ROS generation. NADPH oxidase is the source of ROS in TX stimulated platelets. The proposed model helps explain why an incomplete inhibition of TP receptor results in residual platelet activation, and define new targets for antiplatelet treatment.

Resistant hypertension, is a clinical condition that may confer high cardiovascular risk. Aim of the observational study was to evaluate the prevalence of resistant hypertension, and the association with cardiovascular risk factors or diseases in the Verona urban area. Eleven family doctors retrieved anonymised data concerning blood pressure, diagnosis of hypertension and treatments from a population of 17,502 adult subjects. The prevalence of resistant hypertension was estimated considering patients who had been consecutively treated with at least four antihypertensive medications, regardless of blood pressure values. Further search concerning the clinical characteristics associated with resistant hypertension was performed in a random subsample of 55 patients. The prevalence of hypertension was 21.9%, that of resistant hypertension was 2.1%, approximately 10% of the whole hypertensive population. High prevalence of diabetes mellitus (53%) and hyperlipidemia (83%) was found in association with resistant hypertension. As for end organ damage, high prevalence of carotid artery stenosis (45%), ischemic heart disease (43%) and left ventricular hypertrophy (40%) was observed in patients with resistant hypertension. Blood pressure was higher than 140/90 mmHg in 58% of patients in spite of treatment with four or more different antihypertensive drugs. The average age, systolic and pulse pressure were significantly higher in the subgroup of patients with resistant hypertension. Patients with resistant hypertension are characterised by a higher systolic and pulse pressure and a very high attributable cardiovascular risk, due to high prevalence of cardiovascular risk factors and overt organ damage and cardiovascular disease.

Objective:Physical activity plays an important role in preventing obesity and related cardiometabolic risk factors. The six-minute walk test (6MWT) is a clinical sub-maximal, easy and-cost effective test to asses functional capacity utilized also in epidemiological studies as predictor of cardiovasc

Objective:In a retrospective study, the prevalence of preeclampsia in patients with renal FMD was estimated to 52% (Vance et al., 2015). The aim of our study was to assess the prevalence and nature of pregnancy-related complications in patients with FMD.Design and method:A call for participation was

A high intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs), has been associated with reduced levels of blood pressure (BP). Their antihypertensive action may be due to the reduction of the ω-6/ω-3 ratio and the resulting competitive effect of ω-3 as compared to arachidonic acid (an ω-6 PUFA) as a substrate of cytochrome P450 (CYP450) enzymes involved in the production of vasoactive mediators. Some functional polymorphisms (SNPs), in genes which encode for the same enzymes, were associated with hypertension and ischemic stroke in the Malmö Diet and Cancer (MDC), a Swedish urban-based longitudinal study. The aim of this study was to evaluate the effect of the intake of different types of PUFAs on BP change over time (Δ-BP; mean follow-up 16.6±1.5 years; n=3.550 with complete phenotypic data), also considering the interaction with SNPs in genes involved in their metabolism via CYP450.PUFA intakes were collected by a modified diet history method, and functional SNPs in CYP4F2, CYP4A11, CYP2J2 and EPHX2 were genotyped by Taqman.We did not find any overall association between ω-6 and ω-3 PUFA intakes, or their ratio, with Δ-BP but observed an interaction between CYP4F2 V433M genotype and total omega-3, α-linolenic acid and linoleic/α-linolenic ratio, so that a higher ω-3 PUFA intake was significantly associated with a more pronounced BP decrease over time in subjects with the 433VV genotype (-0.041±0.018 mmHg/year; p=0.024; p-interaction=0.031) CONCLUSIONS: Our data do not support a major role of ω-6 or ω-3 PUFA intakes on BP change over time, but suggest a possible interaction of ω-3 PUFA with the CYP4F2 V433M.

Omega-3 polyunsatured fatty acids (ω-3 PUFA) are essential nutrients mainly derived from fish and seafood but present also in vegetables such as nuts and seed-oils. Some epidemiological and clinical studies indicate a protection of ω-3 FA against cardiovascular disease and a favourable effect on cardiovascular risk factors control in adults. The evidences of their effects in children and adolescents are scanty but a possible beneficial role, especially for insulin sensitivity and blood pressure control, has been proposed. In this review we want to focus especially on the evidences, which could justify the assumption of ω-3 in children and adolescents, and to underline the aspects which need further investigation. Mechanisms through which ω-3 FA act are manifolds and still a matter of investigation: beside their interaction with ion channel and their influence on plasma membrane fluidity, probably the main effect is acting as competitor for cytochrome P-450 (CYP) with respect to ω-6 FA. Thus, they can modulate the biosynthesis of eicosanoids and other lipid mediators, which likely exert a protective action. Another suggestive hypothesis is that their beneficial effect is not dependent only on the intake of ω-3 FA, but also on the complex interaction between different nutrients including ω-3 and other FAs with polymorphisms in genes involved in ω-3 FA modulation. This complex interaction has seldom been explored in children and adolescents. Further studies are needed to investigate all these points in order to find a better collocation of ω-3 FA on the available armamentarium for preventive, possibly individualized, medicine.

Loss-of-function mutations of the the ATP-binding cassette-1 (ABCA1) gene are the cause of Tangier disease (TD) in homozygous subjects and familial HDL deficiency (FHD) in heterozygous subjects. These disorders are characterized by reduced plasma HDL-cholesterol (HDL-C) and altered efflux of cholesterol from cells. Previous studies in TD patients and ABCA1−/− murine models reported defects in platelet count, morphology, and function, but the issue is still controversial. We analyzed three subjects with low to very low HDL-C levels due to the loss-of-function mutations of the ABCA1 gene. Two related patients with FHD were heterozygous carriers of two mutations on the same ABCA1 allele; one, with TD, was homozygous for a different mutation. Mild to moderate thrombocytopenia was observed in all the patients. No morphological platelet abnormalities were detected under optical or EM. History of moderate bleeding tendency was recorded only in one of the FHD patients. Only limited alterations in platelet aggregation and activation of the integrin αIIbβ3 were observed in one FHD patient. While α-granule secretion (P-selectin), content, and secretion of platelet δ-granules (serotonin, ATP, and ADP) and thromboxane (TX) A2 synthesis were normal in all the patients, the expression of lysosomal CD63, in response to some agonists, was reduced in TD patients. In conclusion, three patients carrying ABCA1 genetic variants had low platelet count, with the lowest values observed in TD, not associated with major alterations in platelet morphology and response to agonists or bleeding.

Background and aims Magnesium plays an important role in the modulation of vascular tone and endothelial function and can regulate glucose and lipid metabolism. Patients with hypertension, metabolic syndrome (MetS) and diabetes mellitus (T2DM) have low body magnesium content; indeed, magnesium supplementation has been shown to have a positive effect on blood pressure (BP) and gluco-metabolic parameters. The aim of our study was to evaluate the effect of magnesium supplements on hemodynamic and metabolic parameters in healthy men with a positive family history of MetS or T2DM. Methods and results In a randomized, double-blind, placebo-controlled 8-week crossover trial with a 4 week wash-out period, oral supplements of 8.1 mmol of magnesium-pidolate or placebo were administered twice a day to 14 healthy normomagnesemic participants, aged 23–33 years. The primary endpoint was office BP, measured with a semiautomatic oscillometric device. Secondary endpoints included characteristics of the MetS, namely endothelial function, arterial stiffness and inflammation. Plasma and urinary magnesium were measured in all participants while free intracellular magnesium was measured only in a subsample. There was no significant difference in either systolic and diastolic BP in participants post-magnesium supplementation and post-placebo treatment when compared to baseline BP measurements. Further, the metabolic, inflammatory and hemodynamic parameters did not vary significantly during the study. Conclusions Our study showed no beneficial effect of magnesium supplements on BP, vascular function and glycolipid profile in young men with a family history of MetS/T2DM (trial registration at clinicaltrial.gov ID: NCT01181830 ; 12th of Aug 2010).

Key Clinical Message Cutaneous malar rash and kidney involvement has not previously been reported as presenting symptoms of an angioimmunoblastic T-cell lymphoma (AITL). We report a case of a woman with erythematous rash. A PET-CT revealed a lymphadenopathy and splenomegaly. An inguinal lymph node biopsy showed an AITL. There was clinical improvement after prednisone.

Background and aim: Low plasma vitamin D levels have been associated with heart failure (HF). This research attempts to explain the role of vitamin D supplementation on myocar- dial function in elderly patients with HF. Methods and results: Twenty-three chronic HF patients were randomized in a small parallel group, double-blind, placebo-controlled trial. All patients, with a mean age of 74 years and vitamin D levels

Vitamin D deficiency may play a role in the pathogenesis of chronic heart failure (HF), but whether giving patients supplements to raise vitamin D into the normal range improves their survival is not clear. It has been demonstrated that vitamin D deficiency is common in patients with HF, especially the elderly, in obese and in dark skinned people, and that low vitamin D levels are associated with adverse outcome. The epidemiological data have been confirmed by experimental data, which show that knockout mice for the vitamin D receptor developed myocardial hypertrophy and dysfunction. Data from interventional studies are scarce and discordant, and more research is urgently needed to confirm whether add-on supplementation therapy with vitamin D has a role in the management of patients with chronic HF.