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The use of ionising radiation (IR) for medical diagnosis and treatment procedures has had a major impact on the survival of paediatric patients. Although the benefits of these techniques lead to efficient health care, evaluation of potential associated long-term health effects is required. HARMONIC aims to better understand the increased risk of cancer and non-cancer effects after exposure to medical IR in children with cancer treated with modern external beam radiotherapy (EBRT) – radiation energy in MeV range – and in children with cardiac defects diagnosed and treated with cardiac fluoroscopy procedures (CFP) – radiation energy in keV range. The project investigates, among survivors of paediatric cancer, potential endocrine dysfunction, cardiovascular and neurovascular damage, health-related quality of life and second (and subsequent) primary cancer (SPC). The cardiac component builds a pooled cohort of approximately 90 000 paediatric patients who underwent CFP during childhood and adolescence to investigate cancer risk following exposure to IR and explore the potential effects of conditions predisposing to cancer. HARMONIC develops software tools to allow dose reconstruction in both EBRT and CFP to enable epidemiological investigations and future optimisation of treatments. With the creation of a biobank of blood and saliva samples, HARMONIC aims to provide a mechanistic understanding of radiation-induced adverse health effects and identify potential biomarkers that can predict these effects.

Background Cardiogenic shock (CS) is a systemic disorder associated with dismal short-term prognosis. Given its time-dependent nature, mechanical circulatory support may improve survival. Intra-aortic balloon pump (IABP) had gained widespread use because of the easiness to implant and the low rate of complications; however, a randomized trial failed to demonstrate benefit on mortality in the setting of acute myocardial infarction. Acute decompensated heart failure with cardiogenic shock (ADHF-CS) represents a growing resource-intensive scenario with scant data and indications on the best management. However, a few data suggest a potential benefit of IABP in this setting. We present the design of a study aimed at addressing this research gap. Methods and design The Altshock-2 trial is a prospective, randomized, multicenter, open-label study with blinded adjudicated evaluation of outcomes. Patients with ADHF-CS will be randomized to early IABP implantation or to vasoactive treatments. The primary end point will be 60 days patients’ survival or successful bridge to heart replacement therapy. The key secondary end point will be 60-day overall survival; 60-day need for renal replacement therapy; in-hospital maximum inotropic score, maximum duration of inotropic/vasopressor therapy, and maximum sequential organ failure assessment score. Safety end points will be in-hospital occurrence of bleeding events (Bleeding Academic Research Consortium >3), vascular access complications and systemic (noncerebral) embolism. The sample size for the study is 200 patients. Implications The Altshock-2 trial will provide evidence on whether IABP should be implanted early in ADHF-CS patients to improve their clinical outcomes.

This study evaluates among middle-aged subjects with obesity the prevalence of olfactory impairment (OI) with respect to normative values and its correlation with body composition, cognition, sleep quality, and inflammation. In 60 (31 women, 29 men) volunteers with a body mass index ≥ 30 to ≤ 40 kg/m2, aged ≥ 50 to ≤ 70 years, we assessed olfaction by the Sniffin’ Stick test. We measured anthropometrics, body composition and metabolic profiles and evaluated cognition by the MiniMental State Examination (MMSE) and sleep disturbances by the Insomnia Severity Index (ISI). Patients were classified into two groups according to a total olfactory score (odor Threshold, Discrimination, Identification, TDI) below or above the 25th percentile from age and gender-adjusted normative data. Overall, 25 subjects (42%) had OI (TDI

Background Septic shock is a severe form of sepsis marked by hypotension with an ominous outcome despite the introduction of modern intensive care. The aim of the present study is to obtain a panel with biomarkers, echocardiographic and vascular parameters to better risk stratify patients and identify those at higher risk of ominous outcome. Methods Between May 2013 and April 2016, 35 consecutive patients admitted at the Intensive Care Unit (ICU) of ASST Great Metropolitan Hospital Niguarda with the diagnosis of severe sepsis or septic shock were enrolled. All patients underwent rest echocardiography and several circulating biomarkers of myocardial damage or oxidative stress. Results The multivariate Cox’s proportional hazard model showed that the only independent prognostic predictor for 30-day mortality was the angiopoietin-2, (HR 1.017, 95% CI 1.000–1.034; P = 0.049). An angiopoietin-2 concentrations ≥ of 33,418 pg/mL was identified as the optimal threshold for the discrimination between survivors and non survivors at the time of admission in ICU, with a sensitivity of 80% and a specificity of 68%. Conclusions Septic shock has a poor in-hospital outcome even when the best of care is implemented. Among the biochemical parameters angiopoietin was able to identify patients at risk of death. The lowest the value at admission, the highest the risk of in-hospital death. No echocardiographic nor vascular parameter was able to predict outcome in this setting.

We assessed whether high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, expressed by an increased TG/HDL-C ratio, predict coronary atherosclerotic disease (CAD) outcomes in patients with stable angina. We studied 355 patients (60 ± 9 years, 211 males) with stable angina who underwent coronary computed tomography angiography (CTA), were managed clinically and followed for 4.5 ± 0.9 years. The primary composite outcome was all-cause mortality and non-fatal myocardial infarction. At baseline, the proportion of males, patients with metabolic syndrome, diabetes and obstructive CAD increased across TG/HDL-C ratio quartiles, together with markers of insulin resistance, hepatic and adipose tissue dysfunction and myocardial damage, with no difference in total cholesterol or LDL-C. At follow-up, the global CTA risk score (HR 1.06, 95% confidence interval (CI) 1.03–1.09, P = 0.001) and the IV quartile of the TG/HDL-C ratio (HR 2.85, 95% CI 1.30–6.26, P Trial registration. EVINCI study: ClinicalTrials.gov NCT00979199, registered September 17, 2009; SMARTool study: ClinicalTrials.gov NCT04448691, registered June 26, 2020.

On behalf of MAST4HEALTH consortium: et al., [Scope]: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease with poor therapeutic strategies. Mastiha possesses antioxidant/anti-inflammatory and lipid-lowering properties. The authors investigate the effectiveness of Mastiha as a nonpharmacological intervention in NAFLD., [Methods and Results]: Ninety-eight patients with NAFLD in three countries (Greece, Italy, Serbia) are randomly allocated to either Mastiha or Placebo for 6 months, as part of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The authors assess NAFLD severity via magnetic resonance imaging (MRI) scanning and LiverMultiScan technique and evaluate the effectiveness of Mastiha through medical, anthropometric, biochemical, metabolomic, and microbiota assessment. Mastiha is not superior to Placebo on changes in iron-corrected T1 (cT1) and Liver Inflammation Fibrosis score (LIF) in entire patient population; however, after BMI stratification (BMI ≤ 35 kg m-2 and BMI > 35 kg m-2), severely obese patients show an improvement in cT1 and LIF in Mastiha versus Placebo. Mastiha increases dissimilarity of gut microbiota, as shown by the Bray-Curtis index, downregulates Flavonifractor, a known inflammatory taxon and decreases Lysophosphatidylcholines-(LysoPC) 18:1, Lysophosphatidylethanolamines-(LysoPE) 18:1, and cholic acid compared to Placebo., [Conclusion]: Mastiha supplementation improves microbiota dysbiosis and lipid metabolite levels in patients with NAFLD, although it reduces parameters of liver inflammation/fibrosis only in severely obese patients., This project was funded by the European Union’s Horizon 2020 researchand innovation program MAST4HEALTH under the Marie Skłodowska-Curie grant agreement no. 691042.

The hyperproduction of oxidative stress and inflammatory biomarkers, which is paralleled by decreased levels of antioxidant and anti-inflammatory mediators, is part of cellular mechanisms that contribute to the disruption of metabolic homeostasis in obesity. Whether gender-specific alterations and gender-restricted associations in these biomarkers underlie the increased cardiometabolic risk in men compared to women is unclear. We enrolled 31 women and 29 men, aged ≥50 and ≤70 years and with body mass index ≥ 30 and

Objective: To comprehensively assess whether neopterin in urine could be a candidate biomarker for determining the neuroinflammatory status in ALS. Methods: We performed an observational, cross-sectional study in 81 pALS, 68 age- and sex-comparable healthy controls (HC), 14 patients affected by MS and 24 OND patients. ALS patients underwent a neurological evaluation to assess the global functional status evaluated by Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised (ALSFRS-R) and the disease progression rate. Urinary neopterin concentrations were determined by high-performance liquid chromatography method and were recorded at the time of first examination to assess their effect on disease severity and survival. Results: Urinary neopterin was significantly higher in pALS (263.90 [198.71–474.90]) compared to MS (155.28 [131.74–190.38], p =

Background and Aims. Atherosclerosis is an inflammatory disease with long-lasting activation of innate immunity and monocytes are the main blood cellular effectors. We aimed to investigate monocyte phenotype (subset fraction and marker expression) at different stages of coronary atherosclerosis in stable coronary artery disease (CAD) patients. Methods. 73 patients with chronic coronary syndrome were evaluated by CT coronary angiography (CTCA) and classified by maximal diameter stenosis of major vessels into three groups of CAD severity: CAD1 (no CAD/minimal CAD, n°=30), CAD2 (non-obstructive CAD, n°=21), and CAD3 (obstructive CAD, n°=22). Flow cytometry for CD14, CD16, and CCR2 was used to quantify Mon1, Mon2, and Mon3 subsets. Expression of CD14, CD16, CD18, CD11b, HLA-DR, CD163, CCR2, CCR5, CX3CR1, and CXCR4 was also measured. Adhesion molecules and cytokines were quantified by ELISA. Results. Total cell count and fraction of Mon2 were higher in CAD2 and CAD3 compared to CAD1. By multivariate regression analysis, Mon2 cell fraction and Mon2 expression of CX3CR1, CD18, and CD16 showed a statistically significant and independent increase, parallel to stenosis severity, from CAD1 to CAD2 and CAD3 groups. A similar trend was also present for CX3CR1 and HLA-DR expressions on total monocyte population. A less calcified plaque composition was associated to a higher Mon2 expression of CD16 and higher TNF-α levels. IL-10 levels were lower at greater stenosis severity, while the IFN-γ/IL-10 ratio, a marker of a systemic pro-inflammatory imbalance, was directly correlated to stenosis degree and number of noncalcified plaques. Conclusions. The results of this study suggest that a specific pattern of inflammation-correlated monocyte marker expression is associated to higher stenosis severity and less calcified lesions in stable CAD. The clinical trial Identifier is NCT04448691.

Irisin concentrations are decreased in subjects with overt diabetes and upregulated in those with obesity or impaired fasting glucose. However, gender-balanced data in older populations, in whom risk factors commonly culminate in overt cardiovascular disease, are scarce. We assessed in non-diabetic Caucasian subjects with stage I-II obesity in the early aging range (50 to 70 years), the relationship between irisin, body composition and markers of metabolic derangement by gender. In 60 (31 women, 29 men) non-diabetics with a body mass index ≥30 - ≤40 kg/m2, we measured anthropometrics and body composition (Air Displacement Plethysmography). We assayed lipid and glucose profile by routine methods, plasma irisin by ELISA and measured insulin resistance by the HOMA index. Irisin levels were higher in women than in men (161 [105-198]) vs 83 [33-115] ng/ml, P

Objective Supplementation of glutathione (GSH) may be a positive strategy to improve the endogenous antioxidant defense required to counteract many acute and chronic diseases. However, the efficacy of GSH treatment seems to be closely related to type of administration, degree of absorption, and increase of its concentrations. The aim of this study was to test a new sublingual formulation of L-GSH, which enters directly the systemic circulation, to assess its efficacy on circulating biochemical markers of hepatic metabolism, lipid profile, and oxidative stress and on peripheral vascular function compared with placebo in patients with cardiovascular risk factors (CVRF). Methods We enrolled 16 healthy men with CVRF in a double-blinded, randomized placebo-controlled crossover study. At each visit, blood samples were collected for biochemistry analyses and peripheral endothelial function (reactive hyperemia index [RHI]) and stiffness were measured by Endo-PAT2000. Results In the overall population, a decrease in total and low-density lipoprotein cholesterol was highlighted after L-GSH supplementation compared with placebo (P = 0.023 and P = 0.04, respectively). On the contrary, no difference was observed in RHI and oxidative stress markers between L-GSH and placebo in the study population. However, seven participants with baseline abnormal RHI (≤1.67) compared with those with normal RHI showed a significant reduction of arterial stiffness after L-GSH administration, (P = 0.007 and P = 0.037, respectively). Conclusions Supplementation of L-GSH compared with placebo influences the lipid profile of patients with CVRF. Sublingual L-GSH may represent a valid prevention of vascular damage in patients with CVRF and endothelial dysfunction.

In the original publication of the article, the acknowledgment section was not included and provided below in this correction.

The present study aimed to investigate the inter- and intraday repeatability of reactive hyperemia index (RHI) measured by Endo-PAT in healthy volunteers. Interday RHI repeatability was tested in two consecutive days in a group of thirty-one male subjects. Intraday repeatability was investigated at baseline and after 2 and 4 h in a group of sixteen volunteers. Data were evaluated by analysis of variance. Bland–Altman plot, coefficient of variation (CV), coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were measured. While interday RHI repeatability was found to be reliable (CV: 6.0%; CR: 0.51; ICC: 0.77), multiple evaluations within the same day significantly (p

We previously reported that a portion of blueberries reversed endothelial dysfunction induced by acute cigarette smoking. Since smoking-induced endothelial dysfunction is associated with a condition of oxidative stress, we evaluated whether the observed effect was mediated by modulation of markers of oxidative stress and antioxidant defence. Fourteen out of 16 male healthy smokers previously enrolled, participated in a three-armed randomized controlled study with the following experimental conditions: smoking treatment (one cigarette); blueberry treatment (300g of blueberries) + smoking (one cigarette); control treatment (300ml of water with sugar) + smoking (one cigarette). The cigarette was smoked 100min after blueberry/control/water consumption. Each treatment was separated by 1 week of washout period. Plasma vitamin (C, B12 and folate) and aminothiol concentrations, endogenous [formamidopyrimidine-DNA glycosylase (FPG)-sensitive sites] and oxidatively induced DNA damage (resistance to H2O2-induced DNA damage) in peripheral blood mononuclear cells (PBMCs) were measured at baseline and 20, 60, 90, 120min and 24h after smoking. On the whole, analysis of variance did not show a significant effect of treatment on the modulation of markers of oxidative stress and antioxidant defence but revealed an effect of time for plasma concentrations of vitamin C (P = 0.003), B12 (P0.001), folate (P0.001), total cysteine (P = 0.007) and cysteine-glycine (P = 0.010) that increased following the three treatments after smoking. No significant effect of treatment was observed for the levels of FPG-sensitive sites (P0.05) and H2O2-induced DNA damage (P0.05) in PBMCs. In conclusion, the consumption of a single blueberry portion failed to modulate markers of oxidative stress and antioxidant defence investigated in our experimental conditions. Further studies are necessary to elucidate this finding and help clarifying the mechanisms of protection of blueberries against smoking-induced endothelial dysfunction.

Background. In the pathogenesis of atherosclerosis, a central role is represented by endothelial inflammation with influx of chemokine-mediated leukocytes in the vascular wall. Aim of this study was to analyze the effect of different shear stresses on endothelial gene expression and compute gene network involved in atherosclerotic disease, in particular to homeostasis, inflammatory cell migration, and apoptotic processes.Methods. HUVECs were subjected to shear stress of 1, 5, and 10 dyne/cm2in a Flow Bioreactor for 24 hours to compare gene expression modulation. Total RNA was analyzed by Affymetrix technology and the expression of two specific genes (CXCR4 and ICAM-1) was validated by RT-PCR. To highlight possible regulations between genes and as further validation, a bioinformatics analysis was performed.Results. At low shear stress (1 dyne/cm2) we observed the following: (a) strong upregulation of CXCR4; (b) mild upregulation of Caspase-8; (c) mild downregulation of ICAM-1; (d) marked downexpression of TNFAIP3. Bioinformatics analysis showed the presence of network composed by 59 new interactors (14 transcription factors and 45 microRNAs) appearing strongly related to shear stress.Conclusions. The significant modulation of these genes at low shear stress and their close relationships through transcription factors and microRNAs suggest that all may promote an initial inflamed endothelial cell phenotype, favoring the atherosclerotic disease.

Background— Cardiac resynchronization therapy (CRT) can improve ventricular size, shape, and mass and reduce mitral regurgitation by reverse remodeling of the failing ventricle. About 30% of patients do not respond to this therapy for unknown reasons. In this study, we aimed at the identification and classification of CRT responder by the use of genetic variants and clinical parameters. Methods and Results— Of 1421 CRT patients, 207 subjects were consecutively selected, and CRT responder and nonresponder were matched for their baseline parameters before CRT. Treatment success of CRT was defined as a decrease in left ventricular end-systolic volume >15% at follow-up echocardiography compared with left ventricular end-systolic volume at baseline. All other changes classified the patient as CRT nonresponder. A genetic association study was performed, which identified 4 genetic variants to be associated with the CRT responder phenotype at the allelic ( P P ATPIB1 ), rs5443 ( GNB3 ), rs5522 ( NR3C2 ), and rs7325635 ( TNFSF11 ). Machine learning algorithms were used for the classification of CRT patients into responder and nonresponder status, including combinations of the identified genetic variants and clinical parameters. Conclusions— We demonstrated that rule induction algorithms can successfully be applied for the classification of heart failure patients in CRT responder and nonresponder status using clinical and genetic parameters. Our analysis included information on alleles and genotypes of 4 genetic loci, rs3766031 ( ATPIB1 ), rs5443 ( GNB3 ), rs5522 ( NR3C2 ), and rs7325635 ( TNFSF11 ), pathophysiologically associated with remodeling of the failing ventricle.

Several studies have documented the important role of polyphenol-rich foods in the modulation of vascular remodelling and function. This study aimed to evaluate the capacity of a single portion of blueberry (V. corymbosum) to acutely improve peripheral arterial dysfunction in a group of young volunteers. Twenty-four healthy males (12 non-smokers and 12 smokers) were recruited for two different randomized, controlled, crossover pilot acute studies. In the first study, non-smokers were exposed to a control treatment (C; 300 mL of water with sugar) and a blueberry treatment (BB; 300 g of blueberry). In the second study, smokers underwent 3 different protocols: (1) – smoking treatment (S); (2) – control treatment (CS; 300 mL of water with sugar + smoking); (3) – blueberry treatment (BS; 300 g of blueberry + smoking). Each treatment (1 day long) was separated by a one week washout period. Blood pressure, peripheral arterial function (reactive hyperemia index, RHI, a marker of endothelial function) and arterial stiffness (digital augmentation index, dAix and dAix normalized by considering a heart rate of 75 bpm, dAix@75) were measured before and after each treatment. In the first study, the consumption of blueberry and control treatment acutely increased peripheral arterial function in the group of non-smokers. The improvement in RHI was higher and significantly different after blueberry treatment compared to the control treatment (54.8 ± 8.4% BB vs. 28.2 ± 8.3% C; p = 0.01). No effects were observed for markers of arterial stiffness, blood pressure and heart rate. Acute cigarette smoke significantly increased blood pressure and heart rate, while no significant effect was registered in peripheral arterial function and stiffness. The intake of blueberry and control treatment before a cigarette did not counteract the increase in blood pressure and heart rate, while it significantly improved peripheral arterial function. In particular, a significant increase was observed following BS (35.2 ± 7.5% RHI; p = 0.02) and CS treatments (34.6 ± 11.9% RHI; p = 0.02) when compared to only smoking treatment. No difference between BS and CS was detected. In conclusion, the intake of blueberry and control treatments acutely improved peripheral arterial dysfunction both in smoker and in non-smoker subjects. Further studies should be performed to confirm the results obtained and reveal the potential mechanisms of blueberry in the improvement of endothelial function.

It has been suggested that several dietary compounds may improve endothelial dysfunction and oxidative stress induced by smoking. We investigated the effects of acute smoking on blood pressure, heart rate (HR), peripheral arterial function (reactive hyperemia index, RHI), and arterial stiffness in young smokers by Endo-PAT2000. Twenty subjects that smoked an average of 15 cigarettes per day participated in the study. Reactive Hyperemia Index, arterial stiffness, blood pressure and HR were assessed before and after smoking one cigarette. Acute smoking significantly reduced RHI by 28% while increased arterial systolic (+14%) and diastolic (+10%) blood pressure and HR (+13%) at 5 min, while no effect was observed after 30 min. Arterial stiffness was not significantly affected. A significant, positive correlation was found between total serum cholesterol concentration and post-smoking arterial stiffness values. This study demonstrates that acute cigarette smoking impairs RHI and vital signs in young moderate smokers as evaluated through a non-invasive technique. Additionally, the experimental model described, where a decrease of RHI is induced by cigarette smoking, may be useful to study the impact of dietary vasoactive compounds on endothelial function.

It has been suggested that anthocyanin-rich foods may exert antioxidant effects and improve vascular function as demonstrated mainly in vitro and in the animal model. Blueberries are rich sources of anthocyanins and we hypothesized that their intake could improve cell protection against oxidative stress and affect endothelial function in humans. The aim of the study was to investigate the effect of one portion (300 g) of blueberries on selected markers of oxidative stress and antioxidant protection (endogenous and oxidatively induced DNA damage) and of vascular function (changes in peripheral arterial tone and plasma nitric oxide levels) in male subjects. In a randomized cross-over design, separated by a wash out period ten young volunteers received one portion of blueberries ground by blender or one portion of a control jelly. Before and after consumption (at 1, 2, and 24 hours), blood samples were collected and used to evaluate anthocyanin absorption (through mass spectrometry), endogenous and H(2)O(2)-induced DNA damage in blood mononuclear cells (through the comet assay), and plasma nitric oxide concentrations (through a fluorometric assay). Peripheral arterial function was assessed by means of Endo-PAT 2000. Blueberries significantly reduced (P < .01) H(2)O(2)-induced DNA damage (-18%) 1 hour after blueberry consumption compared to control. No significant differences were observed for endogenous DNA damage, peripheral arterial function and nitric oxide levels after blueberry intake. In conclusion, one portion of blueberries seems sufficient to improve cell antioxidant defense against DNA damage, but further studies are necessary to understand their role on vascular function.

The industrial development of a product requires performing a deep analysis to highlight its characteristics useful for future design. The clinical use of a product stimulates knowledge improvement about it in a constant effort of progress. This work shows the biological characterization of CMC composite mesh. CMC polypropylene prosthesis was seeded with Human fibroblast BJ. Samples (cells and medium) were collected at different time points in order to perform different analysis: inflammatory markers quantification; collagens immunohistochemistry; matrix metalloproteinases zimography; extracellular matrix proteomic profile.CMC presented a good cell viability rate and cell growth during the 21 days. The inflammatory profile showed an initial secretion of anti-inflammatory IL-10 and a final increase of pro-inflammatory IL-6. Immunocytochemistry highlighted a similar Collagen type I/type III ratio. The proteomic analysis evidenced the ECM protein content profile composed, mainly, by collagens, fibronectin, laminin. MMPs resulted both expressed when in contact to mesh.CMC shows a good cell biocompatibility and growth. The increase of pro-inflammatory markers could stimulate proliferation, influencing the integration process in human body. Proteomics highlights the ECM modulation by CMC. An integrated investigation of these biological analyses with mechanical data should improve the design process of a new product. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2045-2052, 2017.

We explored the role of oxidative stress and inflammatory molecules as potential Parkinson (PD) biomarkers and correlated biological with non-motor abnormalities (olfactory impairment and dysautonomia), in patients with idiopathic REM behavior disorder (iRBD) (prodromal PD) and established PD.We recruited 11 iRBD and 15 patients with idiopathic PD (HohenYahr 1-3, on L-DOPA and dopamine agonists combination therapy) and 12 age- and sex-matched controls (CTRL). We measured total olfactory score (TOS), autonomic function [deep breathing (DB), lying to standing (LS) and Valsalva manoeuvre (VM) ratios], blood reduced glutathione (Br-GSH), oxidative stress and inflammatory markers (neopterin).Anosmia was similarly prevalent in iRBD (36%) and PD (33%) patients, but absent in CTRL. Orthostatic hypotension was more common among iRBD (73%) and PD (60%) than in CTRL (25%). By univariable ordinal logistic regression, TOS, Br-GSH, LS and VM ratio worsened from CTRL to iRBD and PD groups. Only reduced Br-GSH levels (p=0.037, OR=0.994; 95%CI 0.988-1.000) were independently associated to PD. TOS correlated with Br-GSH (R=0.34, p=0.037), VM ratio (R=0.43, p=0.015), and neopterin (rho=0.39, p=0.016).Reduced systemic antioxidant capacity is found in prodromal and overt PD and may represent, in association with olfactory loss and cardiovascular dysautonomia, a useful biomarker for an integrative, early diagnosis of PD.

This study investigates the impact of early left ventricular (LV)-mechanical unloading on systemic oxidative stress and inflammation in terminal heart failure patients and their impact both on multi organ failure and on intensive care unit (ICU) stay. Circulating levels of urinary 15-isoprostane-F2t (8-epi-PGF2α) and pro-inflammatory markers [plasma interleukin (IL)-6, IL-8, and urinary neopterin, a monocyte activation index] were analyzed in 20 healthy subjects, 22 stable end-stage heart failure (ESHF) patients and in 23 LV assist device (LVAD) recipients at pre-implant and during first post-LVAD (PL) month. Multi-organ function was evaluated by total Sequential Organ Failure Assessment (tSOFA) score. In LVAD recipients the levels of oxidative-inflammatory markers and tSOFA score were higher compared to other groups. After device implantation 8-epi-PGF2α levels were unchanged, while IL-6, and IL-8 levels increased during first week, and at 1 month returned to pre-implant values, while neopterin levels increased progressively during LVAD support. The tSOFA score worsened at 1 PL-week with respect to pre-implant value, but improved at 1 PL-month. The tSOFA score related with IL-6 and IL-8 levels, while length of ICU stay related with pre-implant IL-6 levels. These data suggest that hemodynamic instability in terminal HF is associated to worsening of systemic inflammatory and oxidative milieu that do not improve in the early phase of hemodynamic recovery and LV-unloading by LVAD, affecting multi-organ function and length of ICU stay. This data stimulate to evaluate the impact of inflammatory signals on long-term outcome of mechanical circulatory support.

BACKGROUND Redox aminothiols have been reported to modulate the activity of recombinant metalloproteinases (MMP). The aim of the present study was to investigate the effects of myocardial redox state on the activities of MMP-2 and -9 implicated in cardiac remodeling in end-stage heart failure patients supported by left ventricular assist device (LVAD). METHODS AND RESULTS During heart transplant (HT) surgery, myocardial specimens (MS) from right ventricular walls and LV walls were obtained from 7 LVAD recipients (LVAD group, MS n=35) and from 7 stable HT candidates on medical therapy (MT group, MS n=35). Myocardial MMP-2 and -9 activities and expression, tissue inhibitor of MMP (TIMP)-1 and -4, transforming growth factor (TGF)-β1 and aminothiol concentrations were measured. MMP-2 and -9 activities were evaluated also by incubating MS with different amounts of reduced and oxidized glutathione (GSH). MMP-2 and -9 activities and expression were lower in the LVAD group, whereas myocardial TIMP-1 and -4 concentrations were comparable to those of MT patients. Higher GSH and TGF-β1 concentrations were found in LVAD-recipients. Only GSH concentrations were inversely related to MMP-2 and -9 activities. In vitro, GSH had an inhibitory effect on MMP-2 and -9 activities. CONCLUSIONS LVAD recipients show reduced myocardial MMP-2 and -9 activities and expression when compared to medically treated patients. Changes of myocardial redox state, predominantly GSH-dependent, appear to modulate MMP-2 and -9 activities by an inhibitory effect dependent on thiol content. These data support a role of GSH cycle in modulating the extracellular matrix in end-stage heart failure patients supported by LVAD.

To investigate whether GGT (gamma-glutamyltransferase) is associated to specific redox patterns. GGT, total and reduced aminothiols and malondialdehyde, were measured in 150 subjects (83 males, 48 (39-56) years), with none, one or more risk factors. By univariable analysis GGT was positively associated with age (p =0.001), male gender (p

Background Glutathione (GSH) is an important intravascular scavenger that protects endothelial cells from atherosclerosis. However, it is still unknown whether cardiovascular (CV) events are associated with metabolic and genetic factors, linked to GSH synthesis in an Italian subpopulation, and if a glutamate-cysteine ligase polymorphism within the catalytic subunit (GCLC) could affect blood and plasma GSH concentrations. Methods One hundred subjects, with or without CV risk factors, were enrolled to evaluate plasma and erythrocyte redox status (GSH, homocysteine, cysteine, cysteinylglycine), antioxidant vitamins (α-tocopherol and ascorbate), malondialdehyde, a lipid peroxidation product, and the presence of the GCLC-129 C/T polymorphism; an experimental hyperhomocysteinemia after methionine-induced stimulation of transsulfuration pathway was performed in 91% of enrolled subjects. Clinical, biochemical, and genetic variables were correlated with the presence of CV events (myocardial infarction, transient ischemic attacks, and stroke). Results By multiple logistic regression analysis, male sex ( P = .027), hypertension ( P = .001), and GCLC C/T genotype ( P = .009) were the only variables associated with events. Plasma α-tocopherol content decreased postmethionine in the T allele subjects compared with wild type ( P for time × group interaction=.001). Plasma-reduced GSH level was higher in C/T than in C/C genotype subjects at both time points ( P for group=.03), whereas intracellular GSH concentration did not differ between the 2 genotype groups either at baseline or postmethionine. Conclusions GCLC T allele, together with hypertension and male sex, is associated with CV events in our study population. Moreover, after stimulation of transsulfuration, intracellular GSH content is preserved in T allele subjects, probably by increases in GSH turnover and export, and consumption of α-tocopherol.

Oxidative stress plays a role in the progression of chronic heart failure (CHF), but whether and how ischaemic heart disease (IHD) or non-IHD aetiology may account for differential redox alterations is currently unclear. We assessed the relation between thiol redox state and lipid peroxidation, as a marker of oxidative stress, in patients with CHF of ischaemic or non-ischaemic origin.Blood reduced glutathione, plasma total and reduced cysteine, cysteinylglycine, homocysteine, glutathione, plasma alpha-tocopherol, ascorbic acid, and free malondialdehyde were assessed in 43 CHF heart transplant candidates (24 IHD and 19 non-IHD) and 30 controls matched for age, gender and number of atherosclerotic risk factors.Reduced cysteine was increased in CHF patients compared with controls. The highest levels were found in IHD versus non-IHD patients versus controls. Malondialdehyde levels were significantly higher in IHD patients than in controls, whereas antioxidant vitamins did not differ among the three groups.Specific abnormalities in the thiol pattern are associated with heart failure aetiology in CHF patients. Our findings point to the possible role of reduced cysteine in the progression of chronic IHD to heart failure status, as an additional pro-oxidant stimulus for worsening oxidative stress.

Background Left ventricular assist device (LVAD) implantation has proven effective as a bridge to transplantation in end-stage heart failure patients (ESHFPs), although survival during device support is critical. Oxidative stress has been implicated in the development of heart failure, but the influence of redox state on in-hospital post-LVAD outcome has not been clarified. Methods and Results In this report we describe the oxidant/anti-oxidant profiles of 15 ESHFPs before LVAD placement, 5 of whom did not survive to 1 month, and in 30 subjects without cardiac disease, representing the control group. Conclusions Preliminary findings suggest that adequate activity of the GPx-1–based anti-oxidant system before device placement is associated with patient survival up to 1 month, despite comparable baseline oxidative stress in patients who both survived and died (within 2 weeks post-LVAD).

Background Aminothiols have a critical function as intracellular redox buffers and constitute furthermore an important extracellular redox system. Lipid peroxidation is increased in chronic heart failure (CHF), but the contribution of each thiol to oxidative stress in this syndrome has not been evaluated. Aim To assess the correlation between blood and plasma concentrations of aminothiols and lipid peroxidation as marker of oxidative stress in CHF patients. Methods Blood reduced glutathione (GSH), plasma total and reduced cysteine, cysteinylglycine, homocysteine, GSH, α-tocopherol, ascorbic acid, and free malondialdehyde (MDA) were assessed in samples obtained from 26 CHF heart transplant candidates and 26 age- and gender-matched controls with atherosclerotic risk factors and no history of cardiovascular disease. Results are expressed as median and interquartile range (I–III). Results MDA levels were significantly higher in CHF patients than in controls [1.03 (0.56–1.60) μM vs. 0.70 (0.40–0.83) μM, p =0.006]. Blood reduced GSH concentrations were significantly higher [662 (327–867) μM vs. 416 (248–571) μM, p =0.016], while α-tocopherol levels were significantly lower [15 (13–19) μM vs. 21 (17–32) μM, p =0.001] in CHF patients than in controls. By multivariate logistic regression analysis, the only independent predictors of lipid peroxidation, as expressed by MDA levels ≥1.00 μM, were increased blood GSH concentrations (OR 1.003 per unit, 95% CI 1.001 to 1.006, p =0.008), ischemic (OR 20, 95% CI 2.6 to 155, p =0.004) and non ischemic CHF etiology (OR 11, 95% CI 1.3 to 99, p =0.026). Conclusions Abnormalities in intracellular GSH cycling are associated to increased lipid peroxidation in CHF.

The endothelial dysfunction induced by hyperhomocysteinemia can be reversed by 5-methyltetrahydrofolate (5-MTHF) via homocysteine (Hcy) lowering. An additive antioxidant action of 5-MTHF has been suggested to ameliorate endothelial dysfunction through increased nitric oxide production and superoxide radical scavenging, independent of Hcy lowering. The aim of the study was to assess whether 5-MTHF affects the redox state in hyperhomocysteinemia. We examined the effect of 3 months of oral 5-MTHF treatment (15 mg/day) on the redox pattern in 48 hyperhomocysteinemic subjects compared to 24 untreated hyperhomocysteinemic subjects. By analysis of variance with repeated measures in the 72 subjects, 5-MTHF markedly decreased plasma total Hcy (p-tHcy; P = 0.0001) and blood-total glutathione (GSH; b-tGSH; P = 0.002). By multivariate linear regression in the treated subjects, p-tHcy changes from baseline to 3 months (adjusted by baseline p-tHcy levels) correlated only with changes in reduced cysteinylglycine (P = 0.001). The effects of treatment on Hcy lowering and GSH metabolism were greater in medium than in moderate hyperhomocysteinemia. In conclusion, high-dose 5-MTHF treatment for 3 months ensures marked Hcy lowering to normal values even in subjects with high Hcy levels, and should be the treatment of choice in medium hyperhomocysteinemia. Furthermore, 5-MTHF shows a favorable interaction with GSH metabolism.

Background: Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx). Between immunologic and non-immunologic factors, reactive oxygen species generation has been proposed as pathogenetic mechanism. This study was aimed at evaluating redox status in HTx recipients and verifying whether it could be independently associated with CAV. Methods: Fifty-five consecutive male HTx recipients, median [interquartile range] age 60 yr [50, 64], underwent angiography 67 months [21, 97] after HTx to assess CAV, defined as significant stenosis in ≥1 epicardial vessel or any distal vessel attenuation. All patients underwent blood sampling 89 months [67, 119] after HTx for biochemical (glucose, creatinine, total and LDL cholesterol, and cyclosporin levels) and redox evaluation [plasma reduced and total homocysteine, cysteine, cysteinylglycine, glutathione, blood reduced glutathione (GSHbl) and vitamin E]. Univariate Odds Ratios (OR) with 95% confidence interval (95% CI, highest vs. lowest quartile) were estimated on the basis of a logistic regression analysis between clinical, conventional biochemical and redox data. Only the significant variables at univariate entered into multivariate analysis. Results: CAV was documented in 15 (27%) patients. Univariate analysis showed that time from HTx to angiography (OR 3.97, 95% CI 1.15–14, p = 0.03) and GSHbl (OR 0.31, 95% CI: 0.14–0.70, p = 0.005) were significantly associated with CAV. However, multivariate analysis revealed GSHbl as the only independent predictor of CAV (OR 0.31, 95% CI: 0.13–0.74, p = 0.008). Conclusions: In HTx recipients reduced levels of GSHbl are independently associated with CAV. Given its potent intracellular scavenger properties, GSHbl may serve as a marker of antioxidant defence consumption, favouring CAV development.

Objectives: To assess the link between perfusion, metabolism, and function in viable myocardium before and early after surgical revascularisation. Design: Myocardial blood flow (MBF, thermodilution technique), metabolism (lactate, glucose, and free fatty acid extraction and fluxes), and function (transoesophageal echocardiography) were assessed in patients with critical stenosis of the left anterior descending coronary artery (LAD) before and 30 minutes after surgical revascularisation. Setting: Tertiary cardiac centre. Patients: 23 patients (mean (SEM) age 57 (1.7) years with LAD stenosis: 17 had dysfunctional viable myocardium in the LAD territory, as shown by thallium-201 rest redistribution and dobutamine stress echocardiography (group 1), and six had normally contracting myocardium (group 2). Results: LAD MBF was lower in group 1 than in group 2 (58 (7) v 113 (21) ml/min, p , 0.001) before revascularisation and improved postoperatively in group 1 (129 (133) ml/min, p , 0.001) but not in group 2 (105 (20) ml/min, p = 0.26). Group 1 also had functional improvement in the LAD territory at intraoperative echocardiography (mean regional wall motion score from 2.6 (0.85) to 1.5 (0.98), p , 0.01). Oxidative metabolism, with lactate and free fatty acid extraction, was found preoperatively and postoperatively in both groups; however, lactate and free fatty acid uptake increased after revascularisation only in group 1. Conclusions: MBF is reduced and oxidative metabolism is preserved at rest in dysfunctional but viable myocardium. Surgical revascularisation yields immediate perfusion and functional improvement, and increases the uptake of lactate and free fatty acids.