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Background: We sought to determine the association between cigarette smoking and carotid plaque ultrasound morphology in a multiethnic cohort. Methods: We analyzed 1,743 stroke-free participants (mean age 65.5 ± 8.9 years; 60% women; 18% white, 63% Hispanic, 19% black; 14% current and 38% former smokers, 48% never smoked) from the Northern Manhattan Study using an ultrasound index of plaque echodensity, the Gray-Scale Median (GSM). Echolucent plaque (low GSM) represents soft plaque and echodense (high GSM) more calcified plaque. The mean GSM weighted by plaque area for each plaque was calculated for those with multiple plaques. Quintiles of GSM were compared to no plaque. Multinomial logistic regression models were used to assess associations of cigarette smoking with GSM, adjusting for demographics and vascular risk factors. Results: Among subjects with carotid plaque (58%), the mean GSM scores for quintiles 1-5 were 48, 72, 90, 105, and 128, respectively. Current smokers had over a two fold increased risk of having GSM in quintile 1 (odds ratio (OR) = 2.17; 95% confidence interval (CI), 1.34-3.52), quintile 2 (OR = 2.33; 95% CI, 1.42-3.83), quintile 4 (OR = 2.05; 95% CI, 1.19-3.51), and quintile 5 (OR = 2.13; 95% CI, 1.27-3.56) but not in quintile 3 (OR = 1.18; 95% CI, 0.67-2.10) as compared to never smokers in fully adjusted models. Former smokers had increased risk in quintile 2 (OR = 1.46; 95% CI, 1.00-2.12), quintile 3 (OR = 1.56; 95% CI, 1.09-2.24), quintile 4 (OR = 1.66; 95% CI, 1.13-2.42), and quintile 5 (OR = 1.73; 95% CI, 1.19-2.51), but not in quintile 1 (OR = 1.05; 95% CI, 0.72-1.55). Conclusions: A nonlinear, V-shaped-like relationship between current cigarette smoking and plaque echodensity was observed. Former smokers were at the highest risk for plaques in high GSM quintiles. Thus, current smokers were more likely to have either soft or calcified plaques and former smokers were at greater risk of having only echodense plaques when compared to those who have never smoked. Further research is needed to determine if plaque morphology mediates an association between smoking and clinical vascular events. [ABSTRACT FROM AUTHOR]

Diabetic hyperglycaemia causes endothelial dysfunction mainly by impairing endothelial nitric oxide (NO) production. Moreover, hyperglycaemia activates several noxious cellular pathways including apoptosis, increase in reactive oxygen species (ROS) levels and diminishing Na-K ATPase activity which exacerbate vascular damage. Serum glucocorticoid kinase (SGK)-1, a member of the serine/threonine kinases, plays a pivotal role in regulating NO production through inducible NO synthase activation and other cellular mechanisms. Therefore, in this study, we aimed to investigate the protective role of SGK-1 against hyperglycaemia in human umbilical endothelial cells (HUVECs). We used retrovirus to infect HUVECs with either SGK-1, SGK-1Δ60 (lacking of the N-60 amino acids-increase SGK-1 activity) or SGK-1Δ60KD (kinase-dead constructs). We tested our hypothesis in vitro after high glucose and glucosamine incubation. Increase in SGK-1 expression and activity (SGK-1Δ60) resulted in higher production of NO, inhibition of ROS synthesis and lower apoptosis in endothelial cell after either hyperglycaemia or glucosamine treatments. Moreover, in this study, we showed increased GLUT-1 membrane translocation and Na−K ATPase activity in cell infected with SGK-1Δ60 construct. These results suggest that as in endothelial cells, an increased SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated NO production after different noxae stimuli. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against diabetic vascular disease. [ABSTRACT FROM AUTHOR]

Background: The study of COMT gene polymorphisms in migraine could be of particular interest since impaired catecholaminergic neurotransmission, namely chronic dopaminergic and noradrenergic hypofunction, is a peculiar migraine trait. In this study, for the first time, we focused on the role of COMT rs4818 genetic variant, the polymorphism most strongly affecting COMT activity, in migraine. This study was conducted in a cohort of carefully clinical characterized Caucasian migraineurs recruited in a specifically dedicated migraine biobank, providing also a replication study on rs4680 polymorphism. Findings: Genotyping of rs4680 and rs4818 Catechol-O-Methyltransferase gene polymorphisms was performed on 380 unrelated migraine patients, and 132 healthy subjects matched for age, gender and race-ethnicity, with no clinical evidence or family history of migraine or other neurological diseases. The rs4680 and rs4818 genotypic frequencies did not deviate from those expected for a population in Hardy-Weinberg equilibrium and did not correlate with demographics or clinical migraine features, even when considering migraine subtypes such as dopaminergic migraine, menstrual migraine, and menstrually related migraine. Conclusions: COMT genotype does not influence migraine susceptibility or phenotype, even considering rs4818 polymorphism and peculiar clinical subtypes. This finding prompts to go over COMT to explain catecholamine derangement in migraine, exploring enzymes involved in catecholamines synthesis and catabolism, such as monoamine-oxidase, dopamine beta-hydroxylase, tyrosine-hydroxylase or tyrosine-decarboxylase, among others. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factors (VEGFs) are the key regulators in angiogenesis and have been shown to play a significant role in the progression and prognosis of angiogenesis-related diseases, such as cancer. VEGF inhibitors are a current pharmacological tumoral strategy. However, despite the strong association between aging and cancer incidence and progression, recent findings suggest impaired angiogenesis accompanied by a reduced expression of VEGF in cells derived from aging subjects. Specific variations of VEGF genes have been demonstrated to be genetic determinants for susceptibility, outcome and therapy response, especially for the solid tumors. Considering the complications present in frail elderly patients, analysis of VEGF genetic polymorphisms in these subjects may further help in tailoring an angiogenic pharmacological strategy, and in improving our ability to better understand prognosis during therapy-related to cancer. [ABSTRACT FROM AUTHOR]

The most important goal in the treatment of patients with diabetes is to prevent the risk of cardiovascular disease (CVD), the first cause of mortality in these subjects. Thiazolidinediones (TZDs), a class of antidiabetic drugs, act as insulin sensitizers increasing insulin-dependent glucose disposal and reducing hepatic glucose output. TZDs including pioglitazone, rosiglitazone and troglitazone, by activating PPAR-γ have shown pleiotropic effects in reducing vascular risk factors and atherosclerosis. However, troglitazone was removed from the market due to its hepatoxicity, and rosiglitazone and pioglitazone both have particular warnings due to being associated with heart diseases. Specific genetic variations in genes involved in the pathways regulated by TDZs have demonstrated to modify the variability in treatment with these drugs, especially in their side effects. Therefore, pharmacogenomics and pharmacogenetics are an important tool in further understand intersubject variability per se but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization. [ABSTRACT FROM AUTHOR]

Summary Several markers have been associated with sarcopenia in the elderly, including bioelectrical indices. Phase angle (PhA) is an impedance parameter and it has been suggested as an indicator of cellular death. Thus, the relationship between PhA and muscle mass and strength was investigated in 207 consecutively elderly participants (mean age 76.2 ± 6.7 years) admitted for multidimensional geriatric evaluation. Muscle strength by grip strength using a hand-held dynamometer and muscle mass was measured by bioimpedentiometer. PhA was calculated directly with its arctangent (resistance / reactance × 180° / π). Linear relationship among muscular mass and strength and with clinical and biochemical parameters, including PhA at uni- and multivariate analysis were performed. Linear regression analysis demonstrated that lower level of PhA is associated with reduction in grip strength (y = 3.16 + 0.08x; r = 0.49; p < 0.001), and even more, with muscle mass (y = 3.04 + 0.25x; r = 0.60; p < 0001). Multivariate analysis confirms these relationships (grip strength β = 0.245, p = 0.031; muscular mass β = 0.623, p < 0.01). Thus, PhA is inversely related to muscle mass and strength in elderly subjects and it may be considered a good bioelectrical marker to identify elderly patients at risk of sarcopenia. [ABSTRACT FROM AUTHOR]

nhanced oxidative stress contributes to the pathogenesis of diabetes and its complications. Peroxiredoxin 6 (PRDX6) is a key regulator of cellular redox balance, with the peculiar ability to neutralize peroxides, peroxynitrite, and phospholipid hydroperoxides. In the current study, we aimed to define the role of PRDX6 in the pathophysiology of type 2 diabetes (T2D) using PRDX6 knockout (-/-) mice. Glucose and insulin responses were evaluated respectively by intraperitoneal glucose and insulin tolerance tests. Peripheral insulin sensitivity was analyzed by euglycemic-hyperinsulinemic clamp, and molecular tools were used to investigate insulin signaling. Moreover, inflammatory and lipid parameters were evaluated. We demonstrated that PRDX6-/- mice developed a phenotype similar to early-stage T2D caused by both reduced glucose-dependent insulin secretion and increased insulin resistance. Impaired insulin signaling was present in PRDX6-/- mice, leading to reduction of muscle glucose uptake. Morphological and ultrastructural changes were observed in islets of Langerhans and livers of mutant animals, as well as altered plasma lipid profiles and inflammatory parameters. In conclusion, we demonstrated that PRDX6 is a key mediator of overt hyperglycemia in T2D glucose metabolism, opening new perspectives for targeted therapeutic strategies in diabetes care. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning is emerging as an innovative and novel cytoprotective strategy to counter ischemic vascular disease. At the root of the preconditioning response is the upregulation of endogenous defense systems to achieve ischemic tolerance. Identifying suitable biomarkers to show that a preconditioning response has been induced remains a translational research priority. Preconditioning leads to a widespread genomic and proteonomic response with important effects on hemostatic, endothelial, and inflammatory systems. The present article summarizes the relevant preclinical studies defining the mechanisms of preconditioning, reviews how the human preconditioning response has been investigated, and which of these bioresponses could serve as a suitable biomarker. Human preconditioning studies have investigated the effects of preconditioning on coagulation, endothelial factors, and inflammatory mediators as well as on genetic expression and tissue blood flow imaging. A biomarker for preconditioning would significantly contribute to define the optimal preconditioning stimulus and the extent to which such a response can be elicited in humans and greatly aid in dose selection in the design of phase II trials. Given the manifold biologic effects of preconditioning a panel of multiple serum biomarkers or genomic assessments of upstream regulators may most accurately reflect the full spectrum of a preconditioning response. [ABSTRACT FROM AUTHOR]

Aim The role of atenolol, a non-vasodilating beta-blocker drug, on long-term mortality in hypertensive older adults is still unclear. The aim of the present study was to evaluate long-term mortality in community-dwelling hypertensive older adults taking atenolol. Methods Long-term mortality after 12-year follow up in isolated hypertensive older adults ( n = 972) was analyzed. The patients were stratified in the presence and absence of atenolol use. Systolic, diastolic and pulse arterial pressure were measured. Results Older adults taking atenolol showed a greater mortality and higher pulse arterial pressure values than those not taking atenolol (73.9% vs 55.0%; P = 0.047 and 74.7 ± 14.1 vs 63.0 ± 14.2 mmHg, P < 0.001, respectively). Cox regression analysis showed that atenolol use (hazard risk 1.91; 95% confidence interval 1.04-4.31; P = 0.04) and pulse arterial pressure (hazard risk 1.02; 95% confidence interval 1.01-1.03; P = 0.032) were predictive of long-term mortality. Conclusions Atenolol use was related to increased mortality in community-dwelling hypertensive Older adults. This increase in mortality risk seems to be related to an increase of pulse arterial pressure. Geriatr Gerontol Int 2014; 14: 153-158. [ABSTRACT FROM AUTHOR]

Cardiopulmonary arrest remains as one of the leading causes of death and disability in Western countries. Although ventricular fibrillation (VF) models in rodents mimic the 'square wave' type of insult (rapid loss of pulse and pressure) commonly observed in adult humans at the onset of cardiac arrest (CA), they are not popular because of the complicated animal procedure, poor animal survival, and thermal injury. Here, we present a modified, simple, and reliable VF-induced rat model of CA that will be useful in studying the mechanisms of CA-induced delayed neuronal death, as well as the efficacy of neuroprotective drugs. CA was induced in male Sprague Dawley rats using a modified method of von Planta et al. (J Appl Physiol 65:2641-2647, ). In brief, VF was induced in anesthetized, paralyzed, and mechanically ventilated rats by an alternating current delivered to the entrance of the superior vena cava into the heart. Resuscitation was initiated by administering a bolus injection of epinephrine and sodium bicarbonate followed by mechanical ventilation and manual chest compressions and countershock with a 10-J direct current. Neurological deficit score was higher in the CA group compared to the sham group during early reperfusion periods, suggesting brain damage. Significant damage in the CA1 hippocampus (21 % normal neurons compared to control animals) was observed following histopathological assessment at 7 days of reperfusion. We propose that this method of VF-induced CA in the rat provides a tool to study the mechanism of CA-induced neuronal death without compromising heart functions. [ABSTRACT FROM AUTHOR]

Abstract: Syncope in the elderly is an extremely prevalent clinical condition characterized by high mortality and presence of recurrences. The diagnosis of syncope in the elderly is sometimes difficult and multidimensional geriatric assessment should be carefully administered. Diagnostic algorithms should be applied with attention, although unknown syncope is still frequent. The therapeutic approach to syncope in the elderly is complicated by the high prevalence of neurally-mediated syncope, in which the therapeutic approach is still unknown. The establishment of a “Syncope Unit” has certainly improved the diagnostic-therapeutic approach to patients with syncope, especially in old age where the management is extremely difficult. [Copyright &y& Elsevier]

The development of Biobanks and recent advances in molecular biology have enhanced the possibility to accelerate translational research studies. The Interinstitutional Multidisciplinary BioBank (BioBIM) is organized in a large healthy donors collection and pathology-based biobanks with the aim to provide a service for development of interdisciplinary studies. A new pathology-based biobank has been organized to specifically collect biospecimen from patients affected by migraine, with the final goal to centralize data, collect blood, plasma, serum, DNA and RNA of patients with this disease. The BioBIM is fully equipped for the automation of sampling/processing, storage and tracking of biospecimens. Standard Operating Procedures have been developed for processing and storage phases as well as archive of clinical data. The availability of biospecimens and clinical data will constitute a resource for various research projects. [ABSTRACT FROM AUTHOR]

Stroke is one of the leading causes of death in industrialized countries for people older than 65 years of age. The reasons are still unclear. A reduction of endogenous mechanisms against ischemic insults has been proposed to explain this phenomenon. The "cerebral" ischemic preconditioning mechanism is characterized by a brief episode of ischemia that renders the brain more resistant against subsequent longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. This protective mechanism seems to be reduced with aging both in experimental and clinical studies. Alterations of mediators released and/or intracellular pathways may be responsible for age-related ischemic preconditioning reduction. Agents able to mimic the "cerebral" preconditioning effect may represent a new powerful tool for the treatment of acute ischemic stroke in the elderly. In this article, animal and human cerebral ischemic preconditioning, its age-related difference, and its potential therapeutical applications are discussed [ABSTRACT FROM AUTHOR]

Treatment for chronic heart failure (CHF) is strongly focused on evidence-based medicine. However, large trials are often far away from the 'real world' of geriatric patients and their messages are poorly transferable to the clinical management of CHF elderly patients. Precipitating factors and especially non-cardiac comorbidity may decompensate CHF in the elderly. More importantly, drugs of first choice, such as angiotensin-converting enzyme inhibitors and β-blockers, are still underused and effective drugs on diastolic dysfunction are not available. Poor adherence to therapy, especially for cognitive and depression disorders, worsens the management. Electrical therapy is indicated, but attention to the older age groups with reduced life expectancy has to be paid. Physical exercise, stem cells, gene delivery, and new devices are encouraging, but definitive results are still not available. Palliative care plays a key role to the end-stage of the disease. Follow-up of CHF elderly patient is very important but tele-medicine is the future. Finally, self-care management, caregiver training, and multidimensional team represent the critical point of the treatment for CHF elderly patients. [ABSTRACT FROM AUTHOR]

Elderly subjects are characterized by a high prevalence of diabetes and clinical frailty. This study aimed to examine the predictive role of clinical frailty on long-term mortality in elderly subjects with and without diabetes. The study evaluated mortality after 12-year follow-up in 188 subjects with diabetes and 1,100 subjects without diabetes selected in 1992. Clinical frailty was assessed according to the 'Frailty Staging System' and stratified in tertiles. After 12-year follow-up, mortality was 50.5 % in subjects without and 66.5 % in subjects with diabetes ( p < 0.001). With increasing frailty, mortality increases from 57.9 to 79.0 % ( p for trend <0.01) in subjects without and from 75.9 to 87.0 % in subjects with diabetes ( p for trend <0.001). Multivariate analysis shows that both diabetes (hazard ratio = 1.38; 95 % confidence interval = 1.12-1.95; p = 0.02) and frailty score (hazard ratio = 1.58 for each unit of increase; 95 % confidence interval = 1.41-2.35; p = 0.04) are predictive of long-term mortality. Moreover, when Cox regression analysis was performed by selecting sex, frailty increases the risk of long-term mortality for each unit of increase by 14 % (hazard ratio = 1.14; 95 % confidence interval = 1.10-1.18; p < 0.01) in women and by 60 % in men (hazard ratio = 1.60; 95 % confidence interval = 1.21-2.12; p < 0.001) in the absence and by 31 % (Hazard ratio = 1.31, 95 % confidence interval = 1.03-1.85, p = 0.03) in women and by 60 % in men (hazard ratio = 1.99, 95 % confidence interval = 1.75-3.05, p < 0.001) in the presence of diabetes, respectively. We concluded that diabetes predicts long-term mortality in elderly subjects. Moreover, clinical frailty significantly predicts mortality in subjects without and even more in those with diabetes. This phenomenon is particularly evident in men. Thus, clinical frailty may be considered a new prognostic factor to identify subjects with diabetes at high risk of mortality. [ABSTRACT FROM AUTHOR]

Objective: Sirtuins (SIRTs) and mitochondrial uncoupling proteins (UCPs) have been implicated in cardiovascular diseases through the control of reactive oxygen species production. This study sought to investigate the association between genetic variants in the SIRT and UCP genes and carotid plaque. Methods: In a group of 1018 stroke-free subjects from the Northern Manhattan Study with high-definition carotid ultrasonography and genotyping, we investigated the associations of 85 single nucleotide polymorphisms (SNPs) in the 11 SIRT and UCP genes with the presence and number of carotid plaques, and evaluated interactions of SNPs with sex, smoking, diabetes and hypertension as well as interactions between SNPs significantly associated with carotid plaque. Results: Overall, 60% of subjects had carotid plaques. After adjustment for demographic and vascular risk factors, T-carriers of the SIRT6 SNP rs107251 had an increased risk for carotid plaque (odds ratio, OR = 1.71, 95% CI = 1.23-2.37, Bonferroni-corrected p = 0.03) and for a number of plaques (rate ratio, RR = 1.31, 1.18-1.45, Bonferroni-corrected p = 1.4×10-5), whereas T-carriers of the UCP5 SNP rs5977238 had an decreased risk for carotid plaque (OR = 0.49, 95% CI = 0.32-0.74, Bonferroni-corrected p = 0.02) and plaque number (RR = 0.64, 95% CI = 0.52-0.78, Bonferroni-corrected p = 4.9×10-4). Some interactions with a nominal p≤0.01 were found between sex and SNPs in the UCP1 and UCP3 gene; between smoking, diabetes, hypertension and SNPs in UCP5 and SIRT5; and between SNPs in the UCP5 gene and the UCP1, SIRT1, SIRT3, SIRT5, and SIRT6 genes in association with plaque phenotypes. Conclusion: We observed significant associations between genetic variants in the SIRT6 and UCP5 genes and atherosclerotic plaque. We also found potential effect modifications by sex, smoking and vascular risk factors of the SIRT/UCP genes in the associations with atherosclerotic plaque. Further studies are needed to validate our observations. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning is the effect of brief ischemic episodes which protect the heart from the following more prolonged ischemic episode. This mechanism is effective in younger but not in aged heart. The age-related reduction of ischemic preconditioning has been demonstrated in experimental models and in elderly patients. Preinfarction angina, a clinical equivalent of ischemic preconditioning, reduces mortality in adult but not in elderly patients with acute myocardial infarction. Physical activity or caloric restriction is partially capable to preserve the cardioprotective effect of ischemic preconditioning in the aging heart. More importantly, physical activity and caloric restriction in tandem action completely preserve the protective mechanism of ischemic preconditioning. Accordingly, the protective mechanism of preinfarction angina is preserved in elderly patients with a high grade of physical activity or a low body-mass index. Thus, both physical activity and caloric restriction are confirmed as powerful anti-aging interventions capable to restore age-dependent reduction of a critical endogenous protective mechanism such as ischemic preconditioning. [ABSTRACT FROM AUTHOR]

Background: comorbidity plays a critical role in the high mortality for chronic heart failure (CHF) in the elderly. Charlson Comorbidity Index (CCI) is the most extensively studied comorbidity index. No studies are available on the ability of CCI to predict mortality in CHF elderly subjects. The aim of the present study was to assess if CCI was able to predict long-term mortality in a random sample of elderly CHF subjects. [ABSTRACT FROM PUBLISHER]

Delayed neuroprotection against ischemic challenges is conferred by both ischemic preconditioning (IPC) and preconditioning by activation of the ɛ-isoform of protein kinase C (ɛPKC-PC). In vivo, ischemic preconditioning enhances GABA release and ameliorates glutamate release during lethal cerebral ischemia. We tested the hypothesis that IPC and ɛPKC-PC confer neuroprotection by GABA synapses in rat organotypic hippocampal slices. Ischemic preconditioning or ɛPKC-PC was induced with 15 mins oxygen-glucose deprivation (OGD) or ψɛRACK, a selective ɛPKC activator; and test ischemia consisted of 40 mins OGD. At the time of peak neuroprotection (48 h after preconditioning), we recorded GABAA receptor-mediated miniature postsynaptic currents (GABA mPSCs) in vulnerable CA1 pyramidal neurons using whole-cell voltage clamp techniques. The frequency and amplitude of GABA mPSCs significantly increased 48 h after IPC. In contrast, ɛPKC-PC enhanced only the amplitude of GABA mPSCs with no effect on frequency. We next asked if neuroprotection depended on these changes in GABA synapses. Weak antagonism of the GABAA receptor with bicuculline (100 nmol/L) decreased the amplitude of GABA mPSCs by 20.9±6.1%. When applied during test ischemia, 100 nmol/L bicuculline abolished neuroprotection conferred by either IPC or ɛPKC-PC. We conclude that neuroprotection conferred by preconditioning depends on functional modifications of GABA synapses.Journal of Cerebral Blood Flow & Metabolism (2009) 29, 375–384; doi:10.1038/jcbfm.2008.126; published online 29 October 2008 [ABSTRACT FROM AUTHOR]

Polyphenols have been widely studied for their antiviral effect against respiratory virus infections. Among these, resveratrol (RV) has been demonstrated to inhibit influenza virus replication and more recently, it has been tested together with pterostilbene against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present work, we evaluated the antiviral activity of polydatin, an RV precursor, and a mixture of polyphenols and other micronutrients, named A5+, against influenza virus and SARS-CoV-2 infections. To this end, we infected Vero E6 cells and analyzed the replication of both respiratory viruses in terms of viral proteins synthesis and viral titration. We demonstrated that A5+ showed a higher efficacy in inhibiting both influenza virus and SARS-CoV-2 infections compared to polydatin treatment alone. Indeed, post infection treatment significantly decreased viral proteins expression and viral release, probably by interfering with any step of virus replicative cycle. Intriguingly, A5+ treatment strongly reduced IL-6 cytokine production in influenza virus-infected cells, suggesting its potential anti-inflammatory properties during the infection. Overall, these results demonstrate the synergic and innovative antiviral efficacy of A5+ mixture, although further studies are needed to clarify the mechanisms underlying its inhibitory effect. [ABSTRACT FROM AUTHOR]

Abstract: Background: The aging heart is characterized by structural changes, which are implicated in the development of left ventricular diastolic dysfunction. However, important changes in systolic function may also occur. Left ventricular end-systolic elastance (E es) is a major determinant of cardiac systolic function and ventricular–arterial interaction. Aim: To evaluate left-ventricular E es in elderly subjects compared with adult control subjects. Methods: We studied dilated (DA, n=14) and hypertensive (HA, n=21) cardiomyopathy patients, and both adult control (A, n=25; age 55.6±6.6 years) and elderly (E, n=25; age 76.3±7.1 years) subjects without clinical–instrumental evidence of cardiovascular disease. M-mode, two-dimensional, and pulsed Doppler echocardiogram were performed. Doppler-derived indices of diastolic function were assessed and E es was calculated by a modified single-beat method. Results: E es was reduced in dilated cardiomyopathy (1.32±0.10 mm Hg/ml) and increased in hypertensive cardiomyopathy (3.12±0.33 mm Hg/ml) patients compared to age-matched control subjects (1.96±0.26 mm Hg/ml; p&#60;0.01 and p&#60;0.05, respectively). More importantly, E es was higher in the elderly (2.52±0.70 mm Hg/ml) than in the adult control group (p&#60;0.05) and was linearly correlated with age (r 2=0.639; p&#60;0.0001). Conclusion: Age-related increase in E es, together with diastolic dysfunction, may lead to aging heart decompensation. [Copyright &y& Elsevier]

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1β from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM. [ABSTRACT FROM AUTHOR]

Introduction: Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis involving arterioles, capillaries and postcapillary venules. LCV is generally confined to the skin, with extracutaneous manifestations occurring less frequently. LCV has multiple potential etiologies. Indeed, histological LCV can be found in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex vasculitis, vasculitis associated with systemic diseases (i.e. sarcoidosis, Sjögren's syndrome, rheumatoid arthritis, and systemic lupus erythematosus), or in vasculitis associated with cancer, infections, sepsis and use of certain medications. LCV can also be idiopathic in up to 50% of cases. Case report: Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist used for management of type 2 diabetes mellitus (T2DM), obesity and overweight associated with one or more weight-related comorbidities. A case of drug-induced LCV has already been described with the use of once-daily oral semaglutide. Herein, we describe the first case of skin-limited LCV induced by once-weekly subcutaneous semaglutide in a 73-year-old man with T2DM, who experienced the complete resolution of the skin lesions shortly after the discontinuation of semaglutide therapy. Conclusion: Future prospective studies, adverse event reporting and post-marketing surveillance will certainly contribute to establishing if LCV represents a less rare than expected side effect of both oral and subcutaneous semaglutide formulations. [ABSTRACT FROM AUTHOR]

A protective effect of vegan diets on health outcomes has been observed in previous studies, but its impact on diabetes is still debated. The aim of this review is to assess the relationship between vegan diets and the risk for type 2 diabetes (T2D) along with its effect on glycemic control and diabetes-related complications. In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta–Analyses) guidelines, Pubmed and Cochrane library databases were systematically searched for all relevant studies. Seven observational and eight randomized controlled (RCTs) studies were included. The methodological quality of studies was assessed using the National Institutes of Health quality assessment tool for observational cohort and cross-sectional studies and the Cochrane Risk of Bias Tool for RCTs. We found that a vegan diet is associated with lower T2D prevalence or incidence and in T2D patients decreases high glucose values and improves glucose homeostasis, as reported from the majority of included studies. This approach seems to be comparable to other recommended healthful eating models, but as it may have potential adverse effects associated with the long-term exclusion of some nutrients, appropriate nutritional planning and surveillance are recommended, particularly in specific groups of diabetic patients such as frail elderly, adolescents, and pregnant or breastfeeding women. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is still among the leading causes of death and disability worldwide. The pathogenic mechanisms beyond its development are several and are complex and this is the main reason why a functional therapy is still missed. The beneficial effects of natural compounds against cardiovascular diseases and IS have been investigated for a long time. In this article, we reviewed the association between the most studied polyphenols and stroke protection in terms of prevention, effect on acute phase, and rehabilitation. We described experimental and epidemiological studies reporting the role of flavonols, phenolic acid, and stilbens on ischemic mechanisms leading to stroke. We analyzed the principal animal models used to evaluate the impact of these micronutrients to cerebral blood flow and to molecular pathways involved in oxidative stress and inflammation modulation, such as sirtuins. We reported the most significant clinical trials demonstrated as the persistent use of polyphenols is clinically relevant in terms of the reduction of vascular risk factors for IS, such as Atrial Fibrillation. Interestingly, different kinds of polyphenols provide brain protection by activating different pathways and mechanisms, like inducing antithrombotic effect, such as Honokiol. For this reason, we discussed an appropriate integrative use of them as a possible therapeutic alternative against stroke. [ABSTRACT FROM AUTHOR]

During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval. [ABSTRACT FROM AUTHOR]