Beneficial Effects of Melatonin on Apolipoprotein-E Knockout Mice by Morphological and 18F-FDG PET/CT Assessments.

Atherosclerosis represents one of the main risk factors for the development of cardiovascular diseases. Their etiologies have been studied in recent years in order to better define therapeutic targets for intervention and to identify diagnostic methods. Two different subtypes of macrophages, M1 and M2, have been described in physiological conditions. They can also be found in the atherosclerotic process, where they both have opposite roles in disease progression. Perivascular brown adipose tissue is also involved in inflammation and endothelial damage. In this work, we provide insights into the protective role of melatonin in the atherosclerotic process by morphological and 18F-FDG-PET/CT analyses. In particular, we examined the effects of melatonin on pathways that are linked to atherosclerosis development. We showed that melatonin, by suppressing M1 activity, reduced inflammation and directed macrophage polarization toward the M2 macrophage subtype. Moreover, melatonin preserved the activity of perivascular brown adipose tissue. In addition, 18F-FDG uptake is very high in mice treated with melatonin, confirming that other factors may alter 18F-FDG distribution. In conclusion, we showed that melatonin affects inflammatory pathways that have been linked to atherosclerosis, assessed the relationships of the 18F-FDG PET/CT parameters with macrophage markers and the production of their cytokines, which that have been defined by morphological evaluations

Impact of blood glucose variability on carotid artery intima media thickness and distensibility in type 1 diabetes mellitus

Aims. Diabetes mellitus is characterized by structural and functional alterations of the large- and medium-size arteries. Whether blood glucose variability, i.e. the glycemic oscillations occurring during the 24-h period, represents a risk factor for vascular alterations additional to and independent on HbA1c in type 1 diabetes mellitus is still undefined. The present study was carried out with the aim at investigating the impact of different measures of blood glucose variability on arterial structure and function. We studied 17 non-complicated type 1 diabetic patients (11 males, six females) with an age of 40.8 ± 7.6 years (mean ± SD). In each patient, 24-h glucose profile was obtained by continuous glucose monitoring system and glucose variability was expressed as mean ± SD of 24-h blood glucose levels, mean amplitude of glycemic excursions and postprandial hyperglycemic spikes. Arterial structure and function was measured as carotid IMT and stiffness. Major findings. The different approaches to assessing blood glucose variability well correlated between and with HbA1c. Carotid IMT and stiffness showed significant correlations with age, blood pressure, heart rate and daily insulin intake but a non- significant correlation with blood glucose variability. Principal conclusion. Thus, in type 1 diabetes mellitus, measures of glycemic variability are useful in predicting both actual and long-lasting glycemic control. In absence of diabetes-related complications and of any intima-media thickness alterations, the major predictors of arterial distensibility are represented by traditional risk factors beside glycemic 24-h control. © 2013 Scandinavian Foundation for Cardiovascular Researc

The Niguarda MEWS, a new and refined tool to determine criticality and instability in Internal Medicine Ward and Emergency Medicine Unit

This study compares the effect of the modified early warning score (MEWS) versus a new early warning system (Niguarda MEWS) for detecting instability and criticality in hospital medical departments. A retrospective observational study was conducted in the Internal Medicine ward of Niguarda Ca' Granda Hospital in Milan between November 2013 and October 2014. MEWS and Niguarda-MEWS were gathered using: systolic blood pressure, respiratory frequency, heart rate, temperature, level of consciousness, oxygen saturation, creatinine level, hematocrit level and age. In order to determine if the patient was critical or not the MEWS criticality cut-off value chosen was 3, while in the Niguarda MEWS it was 6. The primary outcome was the correlation between the critical level of the two scores and in-hospital mortality. The secondary endpoint was the correlation between a specific disease and the two scores. In the study, 471 patients were included, using both the MEWS and the Niguarda MEWS score at admittance: 33.4% of patients turned out to be critically ill using the former, 40.98% when using the latter. Therefore, the specificity of scores was 70% for MEWS and 73% for Niguarda MEWS, the sensitivity 58% for MEWS and 63% for Niguarda MEWS, Niguarda MEWS area under the curve (AUC): 0.736, MEWS AUC: 0.670. For the secondary outcome, the new score is higher for genitourinary and respiratory diseases. Niguarda-MEWS could be an optimal tool to detect criticality and instability in order to address the patient to the right level of care

Melatonin atheroprotective effects in vivo

Chronic inflammatory fibro-proliferative changes leading to atherosclerotic plaques are considered hallmark of cardiovascular diseases [1]. Atherosclerosis pathogenesis is a complex entity, which has not been fully understood; however, many studies have demonstrated the role of oxidative stress and inflammation in its development. Melatonin effects on inflammation and oxidative stress process have been demonstrated in the last ten-year literature [2]. However, its role(s) and mechanism(s) of action as a therapeutic tool against atherosclerosis remain largely unexplored. Our aims were to assess the role of melatonin in the onset and developing of atherosclerotic plaques through radiologic and morphometrical tools in 20 apolipoprotein-E knockout (ApoE) mice fed with Western diet (42% calories from fat). 10/20 mice were treated with melatonin (10 mg/kg per os). 18F-FDG PET-CT is a widely used tool to assess inflammatory changes, even before macroscopic changes have taken place. Glucose metabolism is known to be higher in areas of inflammation due to an increased expression of GLUT transporters on the cell membranes both in animals and humans. Using this feature PET/CT is able to determinate metabolic cellular changes and therefore it can be used as biomarker of atherosclerosis. All mice were scanned both before starting melatonin treatment and at the end of the study. After the last scan mice were sacrificed and vascular remodeling, oxidative stress and inflammation at aortic arch level were evaluated. CT-corrected PET datasets were used for computation of SUVmax. Atherosclerotic vascular remodeling, oxidative stress and inflammation levels were significantly more conspicuous in the control cohort, compared to the treated mice (p≤0.05). 18F-FDG PET/CT did not show significant difference in SUVmax. In summary, also in vivo, melatonin may have a protective effect in the atherosclerotic pathogenesis. Flamma S.p.A.-Italy (www.flammagroup.com) provided with melatonin. Financial supports: Fondazione Cariplo e Regione Lombardia “New opportunities and ways towards ERC” (Project 2014-2256) and University of California - Radiology and Biomedical Imaging Nuclear Medicine Section

The Results of the URRAH (Uric Acid Right for Heart Health) Project: A Focus on Hyperuricemia in Relation to Cardiovascular and Kidney Disease and its Role in Metabolic Dysregulation

The relationship between Serum Uric Acid (UA) and Cardiovascular (CV) diseases has already been extensively evaluated, and it was found to be an independent predictor of all-cause and cardiovascular mortality but also acute coronary syndrome, stroke and heart failure. Similarly, also many papers have been published on the association between UA and kidney function, while less is known on the role of UA in metabolic derangement and, particularly, in metabolic syndrome. Despite the substantial number of publications on the topic, there are still some elements of doubt: (1) the better cut-off to be used to refine CV risk (also called CV cut-off); (2) the needing for a correction of UA values for kidney function; and (3) the better definition of its role in metabolic syndrome: is UA simply a marker, a bystander or a key pathological element of metabolic dysregulation?. The Uric acid Right for heArt Health (URRAH) project was designed by the Working Group on uric acid and CV risk of the Italian Society of Hypertension to answer the first question. After the first papers that individuates specific cut-off for different CV disease, subsequent articles have been published responding to the other relevant questions. This review will summarise most of the results obtained so far from the URRAH research project

Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study

International audienceBACKGROUND & AIMS:All oral direct acting antivirals (DAA) have been shown to improve the liver function of patients with decompensated cirrhosis but it is presently unknown whether this clinical improvement may lead to the delisting of some patients. The aim of this study was to assess if and which patients can be first inactivated due to clinically improvement and subsequently delisted in a real life setting.METHODS:103 consecutive listed patients without hepatocellular carcinoma were treated with different DAA combinations in 11 European centres between February 2014 and February 2015.RESULTS:The cumulative incidence of inactivated and delisted patients by competing risk analysis was 15.5% and 0% at 24weeks, 27.6% and 10.3% at 48weeks, 33.3% and 19.2% at 60weeks. The 34 patients who were inactivated showed a median improvement of 3.4 points for MELD (delta MELD, p20:HR=0.042; p<0.0001), delta MELD (HR=1.349; p<0.0001) and delta albumin (HR=0.307; p=0.0069) both assessed after 12weeks of DAA therapy.CONCLUSIONS:This study showed that all oral DAAs were able to reverse liver dysfunction and favoured the inactivation and delisting of about one patient out-of-three and one patient out-of-five in 60weeks, respectively. Patients with lower MELD scores had higher chances to be delisted. The longer term benefits of therapy need to be ascertained.LAY SUMMARY:The excellent efficacy and safety profile of the new drugs against Hepatitis C virus, "direct acting antivirals" or DAAs, have made antiviral therapy possible also for patients with advanced liver disease and for those on the waiting list for liver transplantation (LT). This study shows for the first time that the DAAs may lead to a remarkable clinical improvement allowing the delisting of one patient out of 5

Activin A Induces Langerhans Cell Differentiation In Vitro and in Human Skin Explants

Langerhans cells (LC) represent a well characterized subset of dendritic cells located in the epidermis of skin and mucosae. In vivo, they originate from resident and blood-borne precursors in the presence of keratinocyte-derived TGFβ. Ιn vitro, LC can be generated from monocytes in the presence of GM-CSF, IL-4 and TGFβ. However, the signals that induce LC during an inflammatory reaction are not fully investigated. Here we report that Activin A, a TGFβ family member induced by pro-inflammatory cytokines and involved in skin morphogenesis and wound healing, induces the differentiation of human monocytes into LC in the absence of TGFβ. Activin A-induced LC are Langerin+, Birbeck granules+, E-cadherin+, CLA+ and CCR6+ and possess typical APC functions. In human skin explants, intradermal injection of Activin A increased the number of CD1a+ and Langerin+ cells in both the epidermis and dermis by promoting the differentiation of resident precursor cells. High levels of Activin A were present in the upper epidermal layers and in the dermis of Lichen Planus biopsies in association with a marked infiltration of CD1a+ and Langerin+ cells. This study reports that Activin A induces the differentiation of circulating CD14+ cells into LC. Since Activin A is abundantly produced during inflammatory conditions which are also characterized by increased numbers of LC, we propose that this cytokine represents a new pathway, alternative to TGFβ, responsible for LC differentiation during inflammatory/autoimmune conditions

Pathomorphogenesis of Glycogen-Ground Glass Hepatocytic Inclusions (Polyglucosan Bodies) in Children after Liver Transplantation

Seventeen out of 764 liver biopsies from transplanted (Tx) livers in children showed glycogen-ground glass (GGG) hepatocytic inclusions. The inclusions were not present in pre-Tx or in the explanted or donor’s liver. Under the electron microscope (EM), the stored material within the cytosol appeared as non-membrane-bound aggregates of electron-lucent globoid or fibrillar granules, previously described as abnormally structured glycogen and identified as Polyglucosan bodies (PB). The appearance of GGG in our children was analogous to that of PB-GGG occurring in a number of congenital diseases due to gene mutations such as Lafora’s d., Andersen’s d., Adult Polyglucosan Body Disease and glycogenin deficiency. The same type of GGG was previously reported in the liver of patients undergoing transplants, immunosuppressive or antiblastic treatment. To explore the potential mechanism of GGG formation, we examined whether the drugs after whose treatment this phenomenon was observed could have a role. By carrying out molecular docking, we found that such drugs somehow present a high binding affinity for the active region of glycogenin, implicating that they can inactivate the protein, thus preventing its interaction with glycogen synthase (GS), as well as the maturation of the nascent glycogen towards gamma, beta or alfa glycogen granules. We could also demonstrate that PG inclusions consist of a complex of PAS positive material (glycogen) and glycogen-associated proteins, i.e., glicogenin-1 and -2 and ubiquitin. These features appear to be analogous to congenital GGG, suggesting that, in both cases, they result from the simultaneous dysregulation of glycogen synthesis and degradation. Drug-induced GGG appear to be toxic to the cell, despite their reversibility

Association between Berlin questionnaire index and blood pressure, organ damage and metabolic profilein a general population

Abstract We evaluated the relationships between Berlin questionnaire (BQ) scores, hypertension and other metabolic variables in 598 subjects (age: 65.8 ± 10 years, mean ± SD) enrolled in the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study representative of the general population, treated or untreated with antihypertensive drugs. Two hundred and eleven subjects (35%) had a positive BQ with two or more positive categories of the inquiry. Compared to those without sleep disorders these subjects showed a greater male prevalence (55.9%), worse serum cholesterol, triglycerides and glucose profile, greater body mass index (BMI) (28.9 ± 4.9 vs. 24.9 ± 3.4 kg/m2), higher office (and to a lesser extent 24‐h) BP and HR values, higher serum creatinine values and greater rate of echocardiographic left ventricular (LV) hypertrophy (25% vs. 13%). These differences were not detected when the data analysis was restricted to treated hypertensive patients. Thus, BQ scores allow to identify among subjects belonging to a general population those with elevated BP, organ damage and altered metabolic. When antihypertensive drug treatment is present, however, the approach fails to detect differences between groups with low or high BQ index

Comparison of electrocardiographic versus echocardiographic detection of left ventricular mass changes over time and evaluation of new onset left ventricular hypertrophy

Abstract We assessed the value of 3 electrocardiographic (EKG) voltage criteria in detecting variations of left ventricular mass (LVM) over time, taking echocardiographic (ECHO) LVM as reference, in the Pressioni Arteriose Monitorate E Loro Associazioni study. In 927 subjects (age 47 ± 13 years on entry, 49.9% men) an ECHO evaluation of LVM and EKG suitable for measurement of EKG‐LVH criteria (Sokolow‐Lyon voltage, Cornell voltage and R‐wave voltage in aVL) were available at baseline and at a 2nd evaluation performed 10 years later. Δ (delta) LVM, Δ LVMI, and Δ EKG parameters values were calculated from 2nd evaluation to baseline. The sensitivity of the EKG criteria in the diagnosis of LVH, poor at baseline, becomes even worse after 10 years, reaching very low values. Only the sensitivity of R‐wave amplitude exhibited slight increase over time but with unsatisfactory absolute values. Despite the prevalence of ECHO‐LVH at the 2nd evaluation was threefold increased compared to baseline (29.3% and 33.7% for LVM indexed to BSA and height2.7, respectively), the prevalence of EKG‐LVH was unchanged when evaluated by Sokolow‐Lyon criteria, significantly reduced when assessed by Cornell voltage index, while significantly increased using R‐wave voltage in aVL criteria. Despite an ECHO‐LVM increase over the time, mean EKG changes were of opposite sign, except for R‐wave amplitude in aVL. Our study highlights the discrepancy between ECHO and EKG in monitoring LVM changes over the time, especially for Sokolow‐Lyon and Cornell voltage. Thus, EKG is an unsuitable method for the longitudinal evaluation of LVM variations