Dietary Intake of Flavonoids, Barrett's Esophagus Development, and Esophageal and Gastric Cancer Incidence and Survival

Flavonoids, polyphenolic compounds concentrated in fruits and vegetables, have experimentally demonstrated chemopreventive effects against esophageal and gastric cancer and Barrett's esophagus, a precursor lesion for esophageal adenocarcinoma. Few epidemiologic studies have examined flavonoids and incidence of esophageal and gastric cancers, and none have considered flavonoids with survival. Additionally, only one epidemiologic investigation has reported an inverse association between isoflavone intake and Barrett's esophagus risk, yet no study has considered other flavonoid classes, which are more commonly consumed in the U.S. This ancillary study built upon the U.S. Multi-Center Study (esophageal adenocarcinoma cases n=274, gastric cardia adenocarcinoma cases n=248, esophageal squamous cell carcinoma cases n=191, other gastric adenocarcinoma cases n=341, and frequency-matched controls n=662) and the Study of Reflux Disease (Barrett's esophagus cases n=170 and matched controls n=183). Participants completed a food frequency questionnaire, and responses were linked with USDA Flavonoid Databases and available literature for six flavonoid classes and lignans. Esophageal and gastric cancer cases were followed until 2000 for vital status. Multivariable-adjusted odds ratios (ORs) and hazard ratios (HRs) [95% confidence intervals (CI)] were estimated, comparing highest versus lowest intake quartiles, using logistic and proportional hazards regressions, respectively. Little or no association was found for total flavonoid intake (main sources in this population: black tea, orange/grapefruit juice, and wine) and development or survival for any tumor type. Intake of anthocyanidins, common in wine and fruit juice, was associated with a reduction in the risk of 57% for developing esophageal adenocarcinoma (OR=0.43, 95% CI: 0.29-0.66), 57% for developing squamous cell carcinoma (OR=0.43, 95% CI: 0.26-0.70), and 41% for developing Barrett's esophagus. ORs for isoflavones, for which coffee was the main source, were increased for all cancer types, except esophageal squamous cell carcinoma. A modest increased risk of Barrett's esophagus development was observed for flavones, for which the main dietary source in this population was pizza. Anthocyanidins were associated with decreased risk of mortality for gastric cardia (HR=0.63, 95% CI: 0.42-0.95) and more modestly for esophageal adenocarcinoma (HR=0.87, 95% CI: 0.60-1.26). Our findings, if confirmed, suggest that increased dietary anthocyanidin intake may reduce risk of developing these tumors and improve survival.Doctor of Philosoph

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.

Peer reviewe

Applicazione clinica di una nuova tecnologia multielettrodica circolare per l'ablazione della fibrillazione atriale

Background: Continui sviluppi tecnologici interessano il campo dell’ablazione transcatetere della fibrillazione atriale (FA). Una nuova tecnologia circolare multielettrodica si presenta oggi come potenziale dispositivo per l’isolamento delle vene polmonari (VP) in pazienti con FA parossistica (FAP). Obiettivi: Abbiamo valutato la fattibilità, l’efficacia e la sicurezza della nuova tecnologia multielettrodica circolare nMARQ™ (Biosense Webster, Diamond Bar, USA) per il trattamento della FAP. Contestualmente sono stati confrontati i tempi di procedura e la quantità di liquidi somministrati al paziente per l’irrigazione del catetere in ablazione. Metodologia: Abbiamo incluso 30 pazienti consecutivi con indicazione all’ablazione transcatetere della FA che presentavano una diagnosi di FAP ed un’anatomia normale o minimamente alterata delle VP (4 VP o 4 osti separati), valutata tramite scansioni TC o RMN prima della procedura, in assenza di dilatazione dell’AS. Di questa popolazione un gruppo di 14 pazienti è stato indirizzato all’ablazione con sistema nMARQ™, i restanti 16 pazienti sono stati trattati con sistemi d’ablazione monoelettrodici di comune impiego presso il nostro centro (ThermoCool®/SmartTouch™). Risultati: Nel gruppo nMARQ™ tutte le VP (57) sono state correttamente isolate con un tempo di ablazione di 16 ± 6 min ed un numero di applicazioni di 31 ± 9. Abbiamo ottenuto una significativa riduzione del tempo totale di ablazione (p <0,0001) e del numero di applicazioni necessarie (p = 0,002), rispetto al gruppo di controllo. Non sono state riportate complicanze peri-procedurali. Il volume di liquidi infuso per l’irrigazione del catetere nMARQ™ in ablazione è risultato minore rispetto al controllo (p=0,0188). Conclusioni: L’impiego della nuova tecnologia multielettrodica circolare è risultato fattibile, con una massima efficacia nell’isolamento delle VP, una riduzione dei tempi di ablazione ed un profilo di sicurezza ottimale. Inoltre, è stata riportata una riduzione del volume di liquidi infusi al paziente per l’irrigazione del catetere in ablazione. Tali risultati necessitano di ulteriori studi e di valutazioni a lungo termine per poter essere confermati

Autoimmune Disorders

The present edition entitled "Autoimmune disorders - Pathogenetic aspects" aims to present the current available evidence of etiopathogenetic insights of both systemic and organ specific autoimmune disorders, the crossover interactions among autoimmunity, cardiovascular morbidity and malignancy as well as novel findings in the exciting fields of osteoimmunology and immunology of pregnancy

Cytosolic nucleic acids as new markers of senescence and hyperglycemia-induced inflammation

openAging is characterized by a gradual functional decline resulting from a complex interaction between genetic, epigenetic and stochastic factors and the rate of aging is recognized as the most important risk factor for the development of the most common age-related diseases (ARDs). Research on aging process is currently focused on understanding the molecular mechanisms underlying age-related features accompanying on one hand, the onset of ARDs and on the other hand, the chances to reach a successful aging. A chronic, systemic, low-grade, age-related pro-inflammatory status, called “Inflammaging” is correlated with ARDs development. The two main culprits of inflammaging are the repeated stimulation of immune system over time and the increased burden of senescent cells. Senescent cells are able to modify the microenvironment acquiring a senescence-associated secretory phenotype (SASP). In patients affected by ADRs, the rate of aging process in increased, as well as the burden of senescent cells with SASP. In this scenario, a better understanding of the molecular mechanisms that promote cellular senescence is of basic and clinical relevance. A number of mechanisms promoting senescence have been well characterized. Increasing evidence suggest that nuclear DNA fragility and a sub-functional DNA damage response (DDR) is associated with an increase release of nucleic acids in cytoplasm, including RNA:DNA hybrids. However, only few studies have tempted to assess the pro- or anti-inflammatory effects of this misplaced nucleic acid pool in different cellular models. In this framework, we have analysed the cytoplasmic pool of misplaced nucleic acids in a model of human endothelial cells (HUVECs), in two prototypical stress conditions related to inflammaging, such as “replicative cellular senescence” and “hyperglycemic condition”. A significant increased amount of misplaced nucleic acids was observed in the cytoplasm of senescent cells compared to the younger ones, and in young cells cultured for 1-week in hyperglycemic condition compared to young cells cultured in normoglycemic medium. The cytosolic pool of misplaced nucleic acids is composed of dsDNA, including micronuclei, bubbles and telomere sequences, dsRNA and hybrids. A reduced expression of RNaseH2, the enzyme involved in the degradation of RNA moiety of RNA:DNA hybrids was observed in senescent cells compared to the younger ones and in young cells treated with hyperglycemic medium. The amounts of mis incorporated ribonucleotides, biomarkers od genome instability, were inversely related to RNaseH2 expression level, suggesting that both “senescence” and “hyperglycemic condition” are associated with increased genomic instability. Since the presence of nucleic acids in cytoplasm can activate a number of cytosolic receptors inducing the antiviral response, characterized by increased release of type 1 Interferon (IFN-1), we analysed cGAS/STING/IRF3 axis and IFN-1 expression in “senescence” and “hyperglycemic condition”. Surprisingly, a strong reduction of cGAS expression was observed in senescent cells in normo and hyperglycemic conditions, in association with the absence of IFN-1 modulation, whereas the expression of proinflammatory cytokines, such as IL-1beta, IL-6 and IL-8 was significantly increased. Overall, our results suggest an imbalance between antiviral and proinflammatory response in senescent cells and in young cells under hyperglycemic conditions. Increasing evidence suggest that senescent cells have an enhanced susceptibility to viral infections. We hypothesized that such imbalance between antiviral and proinflammatory responses could be, almost in part, a direct consequence of their ability “to tolerate” a high cytosolic nucleic acids load. Overall, our results pave the way to explain why old subjects, especially the elderly patients affected by diabetes, are more susceptible to adverse outcomes of infectious diseases.L'invecchiamento è caratterizzato da un graduale declino funzionale derivante da una complessa interazione tra fattori genetici e epigenetici insieme ad un'aumentata velocità di invecchiamento, riconosciuta come il fattore di rischio più importante per lo sviluppo delle malattie associate all'età più comuni (ARD). La ricerca sul processo di invecchiamento è attualmente focalizzata sulla comprensione dei meccanismi molecolari alla base delle caratteristiche legate all'età che accompagnano, da un lato, l'insorgenza di ARD e dall'altro, le possibilità di raggiungere un invecchiamento di successo. Uno stato pro-infiammatorio cronico, sistemico, di basso grado e legato all'età, chiamato "Inflammaging" è correlato allo sviluppo degli ARD. I due principali responsabili dell'inflammaging sono la stimolazione ripetuta del sistema immunitario nel tempo e l'aumento del numero di cellule senescenti. Le cellule senescenti sono in grado di modificare il microambiente acquisendo un fenotipo secretorio associato alla senescenza (SASP). Nei pazienti affetti da ADR, la velocità del processo d’invecchiamento è aumentato, così come il numero delle cellule senescenti con SASP. In questo scenario, una migliore comprensione dei meccanismi molecolari che promuovono la senescenza cellulare è di rilevanza di base e clinica. Prove crescenti suggeriscono che la fragilità del DNA nucleare e una risposta sub-funzionale al danno al DNA (DDR) si associano a un aumento del rilascio di acidi nucleici nel citoplasma, inclusi gli ibridi RNA:DNA. In questa cornice, abbiamo analizzato il pool di acidi nucleici rilasciati nel citoplasma in un modello di cellule endoteliali umane (HUVEC), in due condizioni di stress legate all'inflammaging, come la "senescenza replicativa cellulare " e la "condizione iperglicemica". È stata osservata una quantità significativa di acidi nucleici nel citoplasma delle cellule senescenti rispetto a quelle più giovani e nelle cellule giovani coltivate per 1 settimana in condizioni iperglicemiche rispetto alle giovani cellule coltivate in mezzo normoglicemico. Il pool citosolico di acidi nucleici è composto da dsDNA, tra cui micronuclei, bubbles e sequenze telomeriche, dsRNA e ibridi. Una ridotta espressione di RNasi H2, l'enzima coinvolto nella degradazione della componente a RNA degli ibridi RNA:DNA è stato osservato nelle cellule senescenti rispetto a quelle più giovani e nelle cellule giovani trattate con mezzo iperglicemico. Le quantità di ribonucleotidi mal incorporati, biomarcatori dell’instabilità genomica, sono inversamente correlate al livello di espressione di RNasi H2, suggerendo che sia la "senescenza" che la "condizione iperglicemica" sono associate a una maggiore instabilità genomica. Poiché la presenza di acidi nucleici nel citoplasma può attivare un certo numero di recettori citosolici che inducono la risposta antivirale, caratterizzata da un maggiore rilascio di interferone di tipo 1 (IFN-1), abbiamo analizzato l'asse cGAS/STING/IRF3 e l'espressione IFN-1 in "senescenza" e "condizione iperglicemica". Sorprendentemente, una forte riduzione dell'espressione di cGAS è stata osservata nelle cellule senescenti in condizioni normo e iperglicemiche, in associazione con l'assenza di modulazione di IFN-1, mentre l'espressione di citochine pro-infiammatorie, come IL-1 beta, IL-6 e IL-8 è significativamente aumentata. Nel complesso, i nostri risultati suggeriscono uno squilibrio tra la risposta antivirale e pro-infiammatoria nelle cellule senescenti e nelle cellule giovani in condizioni iperglicemiche. Crescenti evidenze suggeriscono che le cellule senescenti hanno una maggiore suscettibilità alle infezioni virali. Abbiamo ipotizzato che tale squilibrio tra risposte antivirali e pro-infiammatorie potrebbe essere, almeno in parte, una conseguenza diretta della loro capacità di "tollerare" un elevato carico di acidi nucleici citosolici.SALUTE DELL'UOMOopenRamini, Debora

Screening, risk stratification, and management of atrial fibrillation

Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with high morbidity and mortality. Major improvements have been made in the diagnosis and management of AF in the past two decades. However, important questions pertaining to the screening, prognosis, risk stratification, and management of AF remain unanswered. This thesis presents original studies addressing knowledge gaps in these aspects of AF. In Chapter 2, using a large cohort of individuals from the UK Biobank, we investigated the association between lung function and incident AF. We observed that reduced ventilatory function was associated with increased risk of AF independently of age, sex, smoking, and several other known AF risk factors. This suggests that individuals with substantial reduction of their lung function might represent an appropriate population for targeted AF screening and ventilatory parameters might improve AF risk prediction. Chapter 3 assesses data related to implantable cardiac monitors (ICM). The first section reports AF diagnostic yield in a real-world cohort of patients receiving prolonged cardiac monitoring with ICM for stroke and unexplained syncope. It indicates that patients with stroke or transient ischemic attack (TIA) have a higher rate of AF detection compared with patients with unexplained syncope. However, this real-world study shows AF detection rates following stroke significantly lower than what has been previously reported. The second section of this chapter summarizes data on AF detection rates across different rhythm monitoring strategies (non-invasive and ICM) in patients with cryptogenic stroke (CS) or embolic stroke of undetermined source (ESUS). It shows that the yield of ICM increases with the duration of monitoring; more than a quarter of patients with CS or ESUS will be diagnosed with AF during follow-up. About one in seven patients have AF detected within a month of mobile cardiac outpatient telemetry, suggesting that a non-invasive rhythm monitoring strategy should be considered before invasive monitoring. Chapters 4 and 5 address risk stratification in patients with AF. Chapter 4 has two sections. The first section is a meta-analysis that comprehensively summarizes data from prospective cohort studies on clinical predictors of stroke in anticoagulant-naïve patients with AF. It shows that although weighted similarly in most risk stratification schemes such as the CHA2DS2-VASc score, the absolute risk of stroke attributable to hypertension, diabetes, vascular disease, and heart failure may not be the same in individual patients. Furthermore, it shows that female sex seems not to be universally associated with stroke or systemic embolism, suggesting that the decision to initiate oral anticoagulation should not be made on the sole basis of female sex as currently recommended by some scientific societies. By compiling evidence from various studies, the second section of this chapter demonstrates that some anatomic and functional cardiac imaging parameters are associated with stroke in patients with AF and therefore, might improve stroke risk stratification in these patients. Chapter 5 presents two systematic reviews and meta-analysis which show that AF and carotid artery disease frequently co-exist, with about one in ten patients with AF who has carotid stenosis, and vice versa; and non-stenotic carotid disease being much more frequent. Moreover, there is an association between carotid atherosclerosis and the risk of stroke in patients with AF, suggesting that the incorporation of carotid atherosclerosis and characteristics of carotid plaques into scoring systems might improve stroke prediction in patients with AF. Taking this further, the last section of this chapter investigates the potential added value of high-risk carotid plaques on stroke risk stratification compared to the classical CHA₂DS₂-VASc score in a prospective cohort of patients with AF. It shows a low prevalence (5.5%) of moderate to severe carotid stenosis (≥ 50%), whereas one in three participants have carotid plaques considered vulnerable or high-risk. Neither the degree of carotid stenosis nor the presence of vulnerable plaques is associated with incident ischemic stroke, suggesting that carotid disease is probably not an important cause of ischemic stroke in this group of patients with AF and therefore, vulnerable carotid plaques might not improve stroke risk stratification in patients with AF. Chapter 6 presents two pooled analyses of data on the prognostic impact of AF on acute coronary syndromes (ACS) and acute pulmonary embolism (aPE). The first section of the chapter shows that AF is common in patients with ACS (one in nine) and that it (especially newly diagnosed AF) is associated with poor short-term and long-term outcomes including re-infarction, heart failure, stroke, acute kidney injury, heart failure, major bleeding, and death. Likewise, the second section of the chapter demonstrates that AF is frequent in patients with aPE (one in eight) and is associated with increased short-term and long-term mortality. Considering this strong prognostic impact of AF in patients with ACS and aPE, its incorporation into risk stratification schemes for these patients should be considered. Furthermore, considering the significant incidence of AF in patients with ACS and aPE, studies are needed to determine the appropriate rhythm monitoring strategies in these patients. Chapters 7-9 focus on sex differences in the management of AF. Chapter 7 analyses data from 142 randomized controlled trials (RCTs) of AF published in top tiers cardiovascular journals and shows that despite recent progress, females remain substantially less represented in RCTs of AF. This raises concern about the generalizability of these trials and the validity of the evidence guiding the treatment of females. Furthermore, primary outcomes are infrequently reported by sex in these RCTs of AF. Considering established benefit of risk factor modification on outcomes in patients with AF, Chapter 8 assesses sex differences in weight-loss, cardiorespiratory fitness gain, and progression and recurrence of AF in patients undergoing aggressive risk factor modification. It shows that despite sex differences in some baseline characteristics, the benefits of weight-loss and fitness gain were favourable for both males and females. However, improvement in fitness had a much greater benefit for total arrhythmia freedom for females, whereas there was a trend towards more common regression from persistent to paroxysmal AF in males. These findings reinforce the need to address lifestyle risk factors to minimize arrhythmia recurrence and reduce symptom severity for all individuals. Finally, Chapter 9 investigates the impact of sex on the clinical profile, utilization of rhythm control therapies, in-hospital mortality, length of stay (LOS), and cost of hospitalization in patients admitted for AF in the United States. It shows similarities and disparities in risk factors for mortality between males and females, and that unlike what has been reported in several previous studies, although women had a relatively higher mortality rate, after risk adjustment, female sex was not a predictor of mortality.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 02

Prevention and Treatment of Atherosclerosis

This open access book is supported by the European Atherosclerosis Society Association (EAS). This follow-up edition of the well-received Handbook volume 'Atherosclerosis: Diet and Drugs' reflects the state-of-the-art and most recent developments in atherosclerosis research. Outstanding international experts give a comprehensive overview of the field covering topics, such as improving the treatment focusing on established targets, novel drug developments addressing pre-defined targets, hypothesis-based and hypothesis-free approaches to unravel novel targets