Evaluation of Blood Lactate among Different Player Roles: A Pilot Study on Competitive Young Male Soccer Players.

BACKGROUND: Soccer match requires anaerobic and aerobic energetic metabolism. The aim of this pilot study was to investigate the changes in blood lactate concentration in young male soccer players in different playing roles at different time points after the soccer match. METHODS: Following an initial screening of 134 young soccer athletes, 8 male athletes (average age of 15.5 ± 5 SD) were chosen for their characteristics similar to those of competitive athletes. Players were categorized as goalkeeper, central defender, central midfielder, and forward. Blood lactate concentrations were determined using a portable device at different times (10 min, 5 and 16 h) after the soccer match by a maximum effort test on a treadmill. The data were analyzed by one-way analysis of variance ANOVA, followed by Bonferroni's post-hoc test. RESULTS: The following results (mean ± SD) were obtained: VO2max (%) 60.33 ± 3.10; blood lactate (mM) end match (10 min) 2.17 ± 0.78, post-match-early (after 5 h) 2.2 ± 0.42, postmatch-late (16 h) 3.2 ± 0.84. ANOVA analysis indicated that the blood LA concentrations at end-match (10 min) and post-match-early (5 h) were statistically significative lower than those determined at post-match-late (16 h) (p < 0.05). CONCLUSION: These results suggest that aerobic mechanisms can also use LA as an energy source, contributing to the reduction of its blood concentration. This effect can be due to reduced maximal work during a soccer match and to the LA removal during exercise at reduced intensity. These data can provide indications for planning suitable training strategies for young male soccer players.

Identification and Characterization of Neuroprotective Properties of Thaumatin-like Protein 1a from Annurca Apple Flesh Polyphenol Extract.

BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are multifactorial neurodegenerative disorders that are mostly treated with drugs inhibiting key enzymes of cholinergic and aminergic neurotransmission, such as acetyl and butyryl cholinesterase (AChE, BuChE) or monoamine oxidases (MAO)-A/B, and of Aß1-40 aggregation. Diet plant components with multitarget functions are promising compounds in the prevention of AD and PD. Our aim was to identify neuroprotective compounds from Annurca apple polyphenol extract (AFPE). METHODS: AFPE was fractionated by gel filtration, and the eluted peaks were subjected to chemical analyses (i.e., RP-HPLC and mass spectrometry), determination of inhibitory enzyme activity and cell effects by MTT, and morphology assays. RESULTS: In AFPE, we identified thaumatin-like protein 1a, belonging to the pathogenesis-related protein (PR) family. This protein showed the best inhibitory activity on AChE, MAO-A (IC50 = 5.53 µM and 1.71 µM, respectively), and Aß1-40 fibril aggregation (IC50 = 9.16 µM), compared to AFPE and other polyphenol-containing fractions. Among the latter, Peak 4 reverted Aß fibril formation (IC50 = 104.87 µM). Moreover, thaumatin-like protein 1a protected AGS and MKN-28 cells from serum-deprivation-induced stress conditions. CONCLUSIONS: We showed that AFPE exerted neuroprotective functions not only through its polyphenols but also through thaumatin-like protein 1a, which acted like a multitarget molecule.

Effect of Hydroxytyrosol Derivatives of Donepezil on the Activity of Enzymes Involved in Neurodegenerative Diseases and Oxidative Damage.

Monoamine oxidase and xanthine oxidase inhibitors represent useful multi-target drugs for the prevention, attenuation, and treatment of oxidative damage and neurodegenerative disorders. Chimeric molecules, constituted by naturally derived compounds linked to drugs, represent lead compounds to be explored for the discovery of new synthetic drugs acting as enzyme inhibitors. We have previously reported that seven hydroxytyrosol-donepezil hybrid compounds play a protective role in an in vitro neuronal cell model of Alzheimer's disease. In this work, we analyzed the effects exerted by the hybrid compounds on the activity of monoamine oxidase A (MAO-A) and B (MAO-B), as well as on xanthine oxidase (XO), enzymes involved in both neurodegenerative disorders and oxidative stress. The results pointed to the identification, among the compounds tested, of selective inhibitors between the two classes of enzymes. While the 4-hydroxy-3-methoxyphenethyl 1-benzylpiperidine-4-carboxylate- (HT3) and the 4-hydroxyphenethyl 1-benzylpiperidine-4-carboxylate- donepezil derivatives (HT4) represented the best inhibitors of MAO-A, with a scarce effect on MAO-B, they were almost ineffective on XO. On the other hand, the 4,5-dihydroxy-2-nitrophenethyl 1-benzylpiperidine-4-carboxylate donepezil derivative (HT2), the least efficient MAO inhibitor, acted like the best XO inhibitor. Therefore, the differential enzymatic targets identified among the hybrid compounds synthesized enhance the possible applications of these polyphenol-donepezil hybrids in neurodegenerative disorders and oxidative stress.

Sub-THz wireless transmission based on graphene-integrated optoelectronic mixer.

Optoelectronics is a valuable solution to scale up wireless links frequency to sub-THz in the next generation antenna systems and networks. Here, we propose a low-power consumption, small footprint building block for 6 G and 5 G new radio wireless transmission allowing broadband capacity (e.g., 10-100 Gb/s per link and beyond). We demonstrate a wireless datalink based on graphene, reaching setup limited sub-THz carrier frequency and multi-Gbit/s data rate. Our device consists of a graphene-based integrated optoelectronic mixer capable of mixing an optically generated reference oscillator approaching 100 GHz, with a baseband electrical signal. We report >96 GHz optoelectronic bandwidth and -44 dB upconversion efficiency with a footprint significantly smaller than those of state-of-the-art photonic transmitters (i.e., <0.1 mm2). These results are enabled by an integrated-photonic technology based on wafer-scale high-mobility graphene and pave the way towards the development of optoelectronics-based arrayed-antennas for millimeter-wave technology.

Hydroxytyrosol-Donepezil Hybrids Play a Protective Role in an In Vitro Induced Alzheimer's Disease Model and in Neuronal Differentiated Human SH-SY5Y Neuroblastoma Cells.

Alzheimer's disease (AD) is the most common neurodegenerative pathology among progressive dementias, and it is characterized by the accumulation in the brain of extracellular aggregates of beta-amyloid proteins and neurofibrillary intracellular tangles consisting of τ-hyperphosphorylated proteins. Under normal conditions, beta-amyloid peptides exert important trophic and antioxidant roles, while their massive presence leads to a cascade of events culminating in the onset of AD. The fibrils of beta-amyloid proteins are formed by the process of fibrillogenesis that, starting from individual monomers of beta-amyloid, can generate polymers of this protein, constituting the hypothesis of the "amyloid cascade". To date, due to the lack of pharmacological treatment for AD without toxic side effects, chemical research is directed towards the realization of hybrid compounds that can act as an adjuvant in the treatment of this neurodegenerative pathology. The hybrid compounds used in this work include moieties of a hydroxytyrosol, a nitrohydroxytyrosol, a tyrosol, and a homovanillyl alcohol bound to the N-benzylpiperidine moiety of donepezil, the main drug used in AD. Previous experiments have shown different properties of these hybrids, including low toxicity and antioxidant and chelating activities. The purpose of this work was to test the effects of hybrid compounds mixed with Aß1-40 to induce fibrillogenesis and mimic AD pathogenesis. This condition has been studied both in test tubes and by an in vitro model of neuronal differentiated human SH-SY5Y neuroblastoma cells. The results obtained from test tube experiments showed that some hybrids inhibit the activity of the enzymes AChE, BuChE, and BACE-1. Cell experiments suggested that hybrids could inhibit fibrillogenesis, negatively modulating caspase-3. They were also shown to exert antioxidant effects, and the acetylated hybrids were found to be more functional and efficient than nonacetylated forms.

Inhibition of Enzymes Involved in Neurodegenerative Disorders and Aß1-40 Aggregation by Citrus limon Peel Polyphenol Extract.

Alzheimer's (AD) and Parkinson's diseases (PD) are multifactorial neurogenerative disorders of the Central Nervous System causing severe cognitive and motor deficits in elderly people. Because treatment of AD and PD by synthetic drugs alleviates the symptoms often inducing side effects, many studies have aimed to find neuroprotective properties of diet polyphenols, compounds known to act on different cell signaling pathways. In this article, we analyzed the effect of polyphenols obtained from the agro-food industry waste of Citrus limon peel (LPE) on key enzymes of cholinergic and aminergic neurotransmission, such as butyryl cholinesterase (BuChE) and monoamine oxidases (MAO)-A/B, on Aß1-40 aggregation and on superoxide dismutase (SOD) 1/2 that affect oxidative stress. In our in vitro assays, LPE acts as an enzyme inhibitor on BuChE (IC50 ~ 73 µM), MAO-A/B (IC50 ~ 80 µM), SOD 1/2 (IC50 ~ 10-20 µM) and interferes with Aß1-40 peptide aggregation (IC50 ~ 170 µM). These results demonstrate that LPE behaves as a multitargeting agent against key factors of AD and PD by inhibiting to various extents BuChE, MAOs, and SODs and reducing Aß-fibril aggregation. Therefore, LPE is a promising candidate for the prevention and management of AD and PD symptoms in combination with pharmacological therapies.

Inhibition of Interleukin-6 Dependent Metalloproteinases-9/2 Expression in Cancer Cells by Diet Polyphenols.

Among inflammatory cytokines, Interleukin-6 (IL-6) is one of the major activators of acute phase response and is also involved in immune response and cancer progression. IL-6 is involved in the up-regulation of enzymes and growth factors acting on the extracellular matrix (ECM) remodelling components in physio-pathological processes. IL-6 enhances the expression of metalloproteases (MMP-)2/9, enzymes that play a key role in ECM degradation and therefore contribute to the process of tumor metastasis. To counteract and/or prevent cancer diseases, many efforts have been devoted to the identification of factors able to inhibit the IL-6-dependent MMP-9/2 expression. Recently, diet polyphenols have been identified as molecules manifesting anti-inflammatory and anti-cancer properties beyond their well-known capacity to promote health on the basis of their antioxidant effects. This review summarizes the recent advances in this field, focusing on the protective effects exerted by diet polyphenols on the proliferation and invasiveness of tumor cells, with specific emphasis on the ability of these molecules to inhibit the IL-6-dependent upregulation of MMP-2/9.

Heart transplantation and anti-HLA antibodY: myocardial dysfunction and prognosis - HeartLAy study.

AIMS: The presence of anti-human leucocyte antigen (HLA) antibodies has been implicated in a higher incidence of complications as well as mortality rate in heart transplantation. The aim of the study was to identify through non-invasive parameters early signs of myocardial dysfunction in the presence of anti-HLA antibodies but without evidence of antibody-mediated rejection (AMR) and its possible prognostic impact. METHODS AND RESULTS: A total of 113 heart-transplanted patients without acute cellular rejection (ACR) and AMR or cardiac allograft vasculopathy (CAV) were prospectively enrolled and divided into two groups ['HLA+' (50 patients) and 'HLA-' (63 patients)], based on the presence of anti-HLA antibodies. Each patient was followed for 2 years after the enrolment, recording episodes of AMR, ACR, CAV, and mortality. Clinical characteristics were similar between the two groups. Among laboratory data, N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin values were significantly higher in the presence of anti-HLA antibodies (P < 0.001 and P = 0.003, respectively). The echocardiographic parameters that showed a statistically significant difference between the two groups were deceleration time of E wave (DecT E, P < 0.001), left ventricular global longitudinal strain (P < 0.001), tricuspid annular plane systolic excursion (P = 0.011), tricuspid S' wave (P = 0.002), and free wall right ventricular longitudinal strain (fwRVLS, P = 0.027), whereas left atrial strain did not differ significantly (P = 0.408). Univariate analysis showed that anti-HLA antibodies were associated with the development of CAV at both 1 and 2 year follow-up [odds ratio (OR) 11.90, 95% confidence interval (CI) 1.43-90.79, P = 0.022 and OR 3.37, 95% CI 1.78-9.67, P = 0.024, respectively]. Bivariate analysis demonstrated that both fwRVLS and DecT E were predictors of CAV development independently from HLA status. CONCLUSIONS: The presence of circulating anti-HLA antibodies is correlated with a mild cardiac dysfunction, even in the absence of AMR, and CAV development. Interestingly, reduced values of DecT E and fwRVLS were predictors of future development of CAV, independently from anti-HLA antibody.

[Exposome: from definition to future challenges.] / Esposoma: dalla definizione alle sfide future.

The exposome concept arises from the need to integrate different disciplines of public health and environmental sciences, mainly including environmental epidemiology, exposure science, and toxicology. The role of the exposome is to understand how the totality of an individual's exposures throughout the lifetime can impact human health. The etiology of a health condition is rarely explained by a single exposure. Therefore, examining the human exposome as a whole becomes relevant to simultaneously consider multiple risk factors and more accurately estimate concurrent causes of different health outcomes. Generally, the exposome is explained through three domains: general external exposome, specific external exposome, and internal exposome. The general external exposome includes measurable population-level exposures such as air pollution or meteorological factors. The specific external exposome includes information on individual exposures, such as lifestyle factors, typically obtained from questionnaires. Meanwhile, the internal exposome encompasses multiple biological responses to external factors, detected through molecular and omics analyses. Additionally, in recent decades, the socio-exposome theory has emerged, where all exposures are studied as a phenomenon dependent on the interaction between socioeconomic factors that vary depending on the context, allowing the identification of mechanisms that lead to health inequalities. The considerable production of data in exposome studies has led researchers to face new methodological and statistical challenges, introducing various approaches to estimate the effect of the exposome on health. Among the most common are regression models (Exposome-Wide Association Study - ExWAS), dimensionality reduction and exposure grouping techniques, and machine learning methods. The significant conceptual and methodological innovation of the exposome for a more holistic evaluation of the risks associated with human health is continuously expanding and will require further investigations related to the application of information obtained from studies into prevention and public health policies.

Phase noise mitigation in photonics-based radio frequency multiplication.

Two photonics-based radio frequency multiplication schemes for the generation of high-frequency carriers with low phase noise are proposed and experimentally demonstrated. With respect to conventional frequency multiplication schemes, the first scheme induces a selective cancelation of phase noise at periodic frequency-offset values, whereas the second scheme provides a uniform 3-dB mitigation of phase noise. The two schemes are experimentally demonstrated for the generation of a 110-GHz carrier by sixfold multiplication of an 18.3-GHz carrier. In both cases, the experimental results confirm the phase noise reduction predicted by theory.

Modelling socioeconomic position as a driver of the exposome in the first 18 months of life of the NINFEA birth cohort children.

BACKGROUND: The exposome drivers are less studied than its consequences but may be crucial in identifying population subgroups with unfavourable exposures. OBJECTIVES: We used three approaches to study the socioeconomic position (SEP) as a driver of the early-life exposome in Turin children of the NINFEA cohort (Italy). METHODS: Forty-two environmental exposures, collected at 18 months of age (N = 1989), were classified in 5 groups (lifestyle, diet, meteoclimatic, traffic-related, built environment). We performed cluster analysis to identify subjects sharing similar exposures, and intra-exposome-group Principal Component Analysis (PCA) to reduce the dimensionality. SEP at childbirth was measured through the Equivalised Household Income Indicator. SEP-exposome association was evaluated using: 1) an Exposome Wide Association Study (ExWAS), a one-exposure (SEP) one-outcome (exposome) approach; 2) multinomial regression of cluster membership on SEP; 3) regressions of each intra-exposome-group PC on SEP. RESULTS: In the ExWAS, medium/low SEP children were more exposed to greenness, pet ownership, passive smoking, TV screen and sugar; less exposed to NO2, NOX, PM25abs, humidity, built environment, traffic load, unhealthy food facilities, fruit, vegetables, eggs, grain products, and childcare than high SEP children. Medium/low SEP children were more likely to belong to a cluster with poor diet, less air pollution, and to live in the suburbs than high SEP children. Medium/low SEP children were more exposed to lifestyle PC1 (unhealthy lifestyle) and diet PC2 (unhealthy diet), and less exposed to PC1s of the built environment (urbanization factors), diet (mixed diet), and traffic (air pollution) than high SEP children. CONCLUSIONS: The three approaches provided consistent and complementary results, suggesting that children with lower SEP are less exposed to urbanization factors and more exposed to unhealthy lifestyles and diet. The simplest method, the ExWAS, conveys most of the information and is more replicable in other populations. Clustering and PCA may facilitate results interpretation and communication.

Interleukin-6 Elevation Is a Key Pathogenic Factor Underlying COVID-19-Associated Heart Rate-Corrected QT Interval Prolongation.

Background: Heart rate-corrected QT interval (QTc) prolongation is prevalent in patients with severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. Recent evidence suggests that the exaggerated host immune-inflammatory response characterizing the disease, specifically interleukin-6 (IL-6) increase, may have an important role, possibly via direct effects on cardiac electrophysiology. The aim of this study was to dissect the short-term discrete impact of IL-6 elevation on QTc in patients with severe COVID-19 infection and explore the underlying mechanisms. Methods: We investigated the following mechanisms: (1) the QTc duration in patients with COVID-19 during the active phase and recovery, and its association with C-reactive protein (CRP) and IL-6 levels; (2) the acute impact of IL-6 administration on QTc in an in vivo guinea pig model; and (3) the electrophysiological effects of IL-6 on ventricular myocytes in vitro. Results: In patients with active severe COVID-19 and elevated IL-6 levels, regardless of acute myocardial injury/strain and concomitant QT-prolonging risk factors, QTc was significantly prolonged and rapidly normalized in correlation with IL-6 decrease. The direct administration of IL-6 in an in vivo guinea pig model acutely prolongs QTc duration. Moreover, ventricular myocytes incubated in vitro with IL-6 show evident prolongation in the action potential, along with significant inhibition in the rapid delayed rectifier potassium current (IKr). Conclusion: For the first time, we demonstrated that in severe COVID-19, systemic inflammatory activation can per se promote QTc prolongation via IL-6 elevation, leading to ventricular electric remodeling. Despite being transitory, such modifications may significantly contribute to arrhythmic events and associated poor outcomes in COVID-19. These findings provide a further rationale for current anti-inflammatory treatments for COVID-19, including IL-6-targeted therapies.

Maternal pesticides exposure in pregnancy and the risk of wheezing in infancy: A prospective cohort study.

INTRODUCTION: Pesticide exposure in pregnancy may have health effects in the offspring. We studied whether maternal pesticides exposure during pregnancy is associated with infant wheezing. METHODS: The study involved 5997 children from the Italian NINFEA birth cohort, whose mothers were recruited during pregnancy between 2005 and 2016. We used questionnaires completed during pregnancy and 6 months after delivery to derive the following indirect measures of exposure: i) Self-reported pesticide use during the first and the third trimester of pregnancy; (ii) Agricultural activities during the same trimesters. We also evaluated the exposure to agricultural pesticides applied near home using the Corine Land Cover inventory to derive the proportion of a 200-metre buffer area around maternal home address covered by agricultural crops and specific crop types (arable land, fruit trees, heterogeneous cultivations). Questionnaires completed when the child turned 18 months reported information on wheezing between 6 and 18 months of age. We estimated the odds ratios of wheezing adjusting for the following maternal characteristics: age, education, parity, asthma, atopy, smoking in pregnancy, region and area of residence, pet ownership during pregnancy. Crops proximity analyses were restricted to residents in rural areas (N = 1674). RESULTS: Agricultural activities during pregnancy were not associated with infant wheezing. Compared to no pesticide use, there was a weak positive association for self-reported use in the third trimester (POR: 1.30; 95 %CI 0.95-1.78) and a stronger association for use in both trimesters (POR: 1.72; 95 %CI 1.11-2.65). The relationship between the proportion of crops around the home address and the risk of infant wheezing, was J-shaped, in particular for fruit trees with the lowest risk for mid values and elevated risk for higher values. CONCLUSION: We found some evidence of association for maternal pesticide use in pregnancy and residential proximity to fruit trees cultivations with infant wheezing.

Is the New EN689 a Better Standard to Test Compliance With Occupational Exposure Limits in the Workplace?

OBJECTIVE: To evaluate the performance of three measurement strategies to test compliance with occupational exposure limits of similarly exposed groups (SEGs): the old and new versions of EN689, and the BOHS-NVvA guidance on measuring compliance. METHODS: Respirable dust exposures concentrations (n = 1383) measured within the member companies of IMA-Europe were used to compare compliance decisions between the three measurement strategies. A total of 210 SEGs of which 158 with repeated measurements were analysed. An R studio OHcomplianceStrategies package was created for the purpose. RESULTS: The old EN689 strategy resulted in the highest number of compliant SEGs in the preliminary tests and statistical test (49-52% and 83%) with lower percentages of compliance with the new EN689 standard (32-44% and 71%). The percentage of non-compliant SEGs was relatively similar between the old and new EN689 for the preliminary tests (1-12% versus 6-11%). However, the new EN689 declared almost twofold more SEGs non-compliant when applying the statistical test (29% versus 17%). The BOHS-NVvA individual test showed results in between the 26% non-compliant SEGs. CONCLUSION: This study showed differences in compliance decisions between the old and new EN689, with the new EN689 being considerably more stringent and resulting in more non-compliant SEGs.

Transient Hypogonadism Is Associated With Heart Rate-Corrected QT Prolongation and Torsades de Pointes Risk During Active Systemic Inflammation in Men.

Background Systemic inflammation and male hypogonadism are 2 increasingly recognized "nonconventional" risk factors for long-QT syndrome and torsades de pointes (TdP). Specifically, inflammatory cytokines prolong, while testosterone shortens the heart rate-corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men, testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of inflammation on QTc. Methods and Results We investigated (1) the levels of sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C-reactive protein and interleukin-6 levels. Reduction of testosterone levels, which also inversely correlated with 17-ß estradiol over time, significantly contributed to inflammation-induced QTc prolongation. In men with TdP, both active systemic inflammation and hypogonadism were frequently present, with significant correlations between C-reactive protein, testosterone, and 17-ß estradiol levels; in these patients, increased C-reactive protein and reduced testosterone were associated with a worse short-term outcome of the arrhythmia. Conclusions During systemic inflammatory activation, interleukin-6 elevation is associated with reduced testosterone levels in males, possibly deriving from an enhanced androgen-to-estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased long-QT syndrome/TdP risk in men.

Inhibition of Interleukin-6-Induced Matrix Metalloproteinase-2 Expression and Invasive Ability of Lemon Peel Polyphenol Extract in Human Primary Colon Cancer Cells.

Among matrix metalloproteinases (MMPs), MMP-9/2 are key enzymes involved in the proteolysis of extracellular matrices in the inflammatory process and in cancer. Since MMP-9/2 expression levels, activity, and secretion is up-regulated during inflammation in response to pro-inflammatory cytokines, such as interleukin-6 (IL-6), many efforts have been devoted to identifying factors that could inhibit the IL-6-induced MMP-9/2 expression. Up to now, several reports indicated that polyphenols from fruits and vegetables are among the major components of health promotion for their antioxidant properties and also for their anti-inflammatory and anti-cancer agents. Among plant derived polyphenols, lemon (Citrus limon) peel extract (LPE) shows anti-cancer properties in various cancer types. In our previous work, we demonstrated that LPE can reduce IL-6-induced migration/invasiveness and MMP-9/2 up-regulation in some gastric cancer cell lines. This study aims to exploit the anti-cancer properties of LPE using an in vitro system model of inflammation, consisting of IL-6-exposed human primary colon cancer cells. We first analyzed the effect of LPE on IL-6-induced cell migration and invasiveness by wound healing and Boyden chamber assay, respectively. The MMP-2 mRNA expression levels and gelatinolytic activity in the cell culture media were determined by q-PCR analysis and gelatin zymography, respectively, and finally, the effects of LPE on IL-6-induced JAK2/STAT3 signaling pathways have been investigated by Western blotting analysis. Our results show that LPE is able to inhibit the IL-6-dependent cell migration and invasiveness associated with the up-regulation of MMP-2 expression levels and that these effects are correlated to the STAT3 phosphorylation in human primary T88 and T93 colon cancer cells.

Unravelling Atrioventricular Block Risk in Inflammatory Diseases: Systemic Inflammation Acutely Delays Atrioventricular Conduction via a Cytokine-Mediated Inhibition of Connexin43 Expression.

Background Recent data suggest that systemic inflammation can negatively affect atrioventricular conduction, regardless of acute cardiac injury. Indeed, gap-junctions containing connexin43 coupling cardiomyocytes and inflammation-related cells (macrophages) are increasingly recognized as important factors regulating the conduction in the atrioventricular node. The aim of this study was to evaluate the acute impact of systemic inflammatory activation on atrioventricular conduction, and elucidate underlying mechanisms. Methods and Results We analyzed: (1) the PR-interval in patients with inflammatory diseases of different origins during active phase and recovery, and its association with inflammatory markers; (2) the existing correlation between connexin43 expression in the cardiac tissue and peripheral blood mononuclear cells (PBMC), and the changes occurring in patients with inflammatory diseases over time; (3) the acute effects of interleukin(IL)-6 on atrioventricular conduction in an in vivo animal model, and on connexin43 expression in vitro. In patients with elevated C-reactive protein levels, atrioventricular conduction indices are increased, but promptly normalized in association with inflammatory markers reduction, particularly IL-6. In these subjects, connexin43 expression in PBMC, which is correlative of that measured in the cardiac tissue, inversely associated with IL-6 changes. Moreover, direct IL-6 administration increased atrioventricular conduction indices in vivo in a guinea pig model, and IL-6 incubation in both cardiomyocytes and macrophages in culture, significantly reduced connexin43 proteins expression. Conclusions The data evidence that systemic inflammation can acutely worsen atrioventricular conduction, and that IL-6-induced down-regulation of cardiac connexin43 is a mechanistic pathway putatively involved in the process. Though reversible, these alterations could significantly increase the risk of severe atrioventricular blocks during active inflammatory processes.

Survival in acute heart failure in intensive cardiac care unit: a prospective study.

The aim of this study is to identify the best predictors of mortality among clinical, biochemical and advanced echocardiographic parameters in acute heart failure (AHF) patients admitted to coronary care unit (CCU). AHF is a clinical condition characterized by high mortality and morbidity. Several studies have investigated the potential prognostic factors that could help the risk assessment of cardiovascular events in HF patients, but at the moment it has not been found a complete prognostic score (including clinical, laboratory and echocardiographic parameters), univocally used for AHF patients. Patients (n = 118) admitted to CCU due to AHF de novo or to an exacerbation of chronic heart failure were enrolled. For each patient, clinical and biochemical parameters were reported as well as the echocardiographic data, including speckle tracking echocardiography analysis. These indexes were then related to intra- and extrahospital mortality. At the end of the follow-up period, the study population was divided into two groups, defined as 'survivors' and 'non-survivors'. From statistical analysis, C-reactive protein (CRP) (AUC = 0.75), haemoglobin (AUC = 0.71), creatinine clearance (AUC = 0.74), left atrial strain (AUC = 0.73) and freewall right ventricular strain (AUC = 0.76) showed the strongest association with shortterm mortality and they represented the items of the proposed risk score, whose cut-off of 3 points is able to discriminate patients at higher risk of mortality. AHF represents one of the major challenges in CCU. The use of a combined biochemical and advanced echocardiographic score, assessed at admission, could help to better predict mortality risk, in addition to commonly used indexes.

Cardiac Arrest Risk During Acute Infections: Systemic Inflammation Directly Prolongs QTc Interval via Cytokine-Mediated Effects on Potassium Channel Expression.

BACKGROUND: During acute infections, the risk of malignant ventricular arrhythmias is increased, partly because of a higher propensity to develop QTc prolongation. Although it is generally believed that QTc changes almost exclusively result from concomitant treatment with QT-prolonging antimicrobials, direct effects of inflammatory cytokines on ventricular repolarization are increasingly recognized. We hypothesized that systemic inflammation per se can significantly prolong QTc during acute infections, via cytokine-mediated changes in K+ channel expression. METHODS: We evaluated (1) the frequency of QTc prolongation and its association with inflammatory markers, in patients with different types of acute infections, during active disease and remission; (2) the prevalence of acute infections in a cohort of consecutive patients with Torsades de Pointes; (3) the relationship between K+ channel mRNA levels in ventricles and peripheral blood mononuclear cells and their changes in patients with acute infection over time. RESULTS: In patients with acute infections, regardless of concomitant QT-prolonging antimicrobial treatments, QTc was significantly prolonged but rapidly normalized in parallel to CRP (C-reactive protein) and cytokine level reduction. Consistently in the Torsades de Pointes cohort, concomitant acute infections were highly prevalent (30%), despite only a minority (25%) of these cases were treated with QT-prolonging antimicrobials. KCNJ2 K+ channel expression in peripheral blood mononuclear cell, which strongly correlated to that in ventricles, inversely associated to CRP and IL (interleukin)-1 changes in acute infection patients. CONCLUSIONS: During acute infections, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless concomitant antimicrobial therapy. Although transient, these changes may significantly increase the risk of life-threatening ventricular arrhythmia in these patients. It is timely and warranted to transpose these findings to the current coronavirus disease 2019 (COVID-19) pandemic, in which both increased amounts of circulating cytokines and cardiac arrhythmias are demonstrated along with a frequent concomitant treatment with several QT-prolonging drugs. Graphic Abstract: A graphic abstract is available for this article.

Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes.

BACKGROUND: Men normally have shorter heart rate-corrected QT interval (QTc) than women, at least in part due to accelerating effects of testosterone on ventricular repolarization. Accumulating data suggest that androgen-deprivation therapy (ADT) used for the treatment of prostatic cancer, may increase Torsades de Pointes (TdP) risk by prolonging QTc. However, the evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases. OBJECTIVE: To better determine the clinical impact of ADT on TdP development, we examined the prevalence of this therapy in a consecutive cohort of 66 TdP patients, prospectively collected over a ~10 years period. METHODS AND RESULTS: We found and described four patients who were under ADT for prostatic cancer when TdP occurred, and in two cases degenerated to cardiac arrest. Notably, in this unselected population, ADTs unexpectedly represented the second most frequently administered QT-prolonging medication in males (4/24, 17%), after amiodarone. Moreover, in the ADT patients, a blood withdrawal was performed within 24 h from TdP/marked QTc prolongation occurrence and circulating concentration of androgens and gonadothropins were measured. As expected, all cases showed markedly reduced testosterone levels (total, free, and available). CONCLUSION: We provide evidence that a significant proportion of patients developing TdP were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals. An accurate assessment of the arrhythmic risk profile should be included in the standard of care of prostatic cancer patients before starting ADT.