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ObjectiveAfter a previous survey on the incidence of diabetic ketoacidosis (DKA) at onset of type 1 diabetes in children in 2013–2014 in Italy, we aimed to verify a possible decline in the incidence of DKA at onset during a national prevention campaign.DesignProspective observational study.SettingMulticentre study throughout Italy.InterventionNational awareness campaign started in November 2015 and held until December 2017.PatientsDuring 2016 and 2017 we collected data on all patients aged 0–18 years with new-onset diabetes.Main outcome measuresDKA (pH ResultsRecords (n=2361) of children with newly diagnosed type 1 diabetes were collected from 58 out of 68 (85.3%) centres of the original survey participants and 100% of the previously surveyed tertiary centres. Overall, DKA was observed in 1124 patients, with an increased rate when compared with the previous survey (47.6% vs 38.5%, p=0.002), and severe DKA in 15.3%. In children below 6 years, DKA was observed in 323 out of 617 (52.5%) and severe DKA in 16.7%; in this age group, occurrence of DKA reduced by 21.3% (p=0.009). DKA treatment according to the ISPED guidelines was adopted in 95% of the centres, with a 27% improvement (p=0.025).ConclusionsDuring a 2-year awareness campaign, DKA at onset of diabetes in children and adolescents 0–18 years is still common and increased when compared with the 2013–2014 survey.

L’Organizzazione Mondiale della Sanità (OMS) ha recentemente stigmatizzato l’abitudine al fumo come una delle più gravi emergenze sanitarie globali. I dispositivi elettronici per il rilascio di nicotina (DERN), o sigarette elettroniche (e-cigs) sono state immesse sul mercato proprio con lo scopo di fornire al soggetto fumatore la possibilità di assumere nicotina esalando vapore, da un sistema che non prevede la combustione, e proposti al pubblico come metodi a “ridotto rischio per la salute”. Largamente diffusi, specialmente tra i più giovani, in alcuni paesi sono stati addirittura inclusi nei programmi integrati di lotta al tabagismo. Tuttavia, ad oggi, alcuni prestigiosi enti scientifici come il National Institute for Health and Care Excellence (NICE) ha ribadito come i dati sui possibili effetti tossicologici siano ancora limitati esortando la comunità scientifica a condurre studi indipendenti. Negli ultimi anni il nostro gruppo di ricerca ha studiato alcuni aspetti tossicologici associati all’esposizione dei vapori di e-cigs nel modello animale. Abbiamo rilevato aldeidi tossiche nello svapato e nei polmoni di ratto esposto per 4 settimane ed è stato osservato un marcato incremento degli enzimi del metabolismo degli xenobiotici, elevate concentrazione di radicali liberi (ROS), e una inattivazione dei principali enzimi antiossidanti in linea con i marcatori di danno ossidativo a livello sistemico e d’organo (DNA, lipidi, proteine). Test di mutagenesi effettuati su sangue e urine (comet, micronulcei, Ames) hanno evidenziato la potenzialità genotossica associata all’esposizione di e-cig. E’ interessante notare come i risultati delle analisi emocitometriche mostrino l’andamento tipico di pazienti affetti da brocopneumopatie ostruttive (COPD), con un marcato aumento dei neutrofili. I nostri studi hanno inoltre dimostrato come la scelta dell’atomizzatore, quindi del valore di resistenza applicata al sistema, sia inversamente associato alle concentrazioni di ROS e composti carbonilici rilasciati come formaldeide, acetaldeide e acroleina, indipendentemente dal voltaggio applicato. I dati in vivo confermano l’ipotesi di una tossicità direttamente dipendente dal tipo di atomizzatore scelto dal consumatore a parità di condizioni sperimentali. I risultati evidenziano inoltre come resistenze sub-Ohmiche producano un danno più marcato all’epitelio tracheale, mentre a livello polmonare, le immagini di microscopia elettronica mostrano come passando da un atomizzatore a resistenza di 1,5 Ohm a valori sub-Ohmici, il conseguente aumento del vattaggio determini una riduzione del numero e diametro dei bronchioli, fino ad una marcata disorganizzazione del parenchima polmonare con collasso alveolare, presenza di cellule in apoptosi e necrosi. Nel complesso, i risultati suggeriscono come l’utilizzo di e-cig possa costituire un serio rischio per la salute e che la personalizzazione del dispositivo e le modalità di utilizzo influenzino significativamente il rilascio di composti tossici e l’impatto sul sistema respiratorio.

Numerosi studi sperimentali suggeriscono un ruolo chemiopreventivo della vitamina E (VE) nei confronti di numerose patologie tumorali incluso il cancro alla prostata (CA). Tuttavia, le evidenze epidemiologiche più recenti non confermano tale ipotesi, e lo studio clinico SELECT ha addirittura evidenziato un aumento dell’incidenza di CA alla prostata in pazienti sani al momento dell’arruolamento, ai quali era stata somministrata VE giornalmente alla dose di 400 UI/die. Essendo noto in letteratura come alcune isoforme del citocromo P450 (CYP) siano sovra espresse in lesioni prostatiche maligne, e che la VE, agisca come induttore del CYP in alcuni tessuti, abbiamo ipotizzato che l’aumento dell’incidenza di CA possa coinvolgere un meccanismo co-cancerogenico legato all’induzione CYP. L’esposizione a VE produce una marcata induzione del CYP in cellule epiteliali di prostata RWPE-1, incluse le isoforme responsabili dell’attivazione degli Idrocarburi Policiclici Aromatici (IPA), accompagnata da un significativo aumento delle specie reattive dell’ossigeno (ROS). Inoltre, il pathway pro-infiammatorio COX-2-dipendente risulta incrementato, caratteristica che si osserva in diverse forme tumorali incluso quelle che interessano la prostata. Il fenomeno è stato confermato nel modello animale; è stato osservato un aumento delle monoossigenasi e dell’espressione genica di alcune isoforme CYP a livello prostatico unito a una maggiore concentrazione di ROS, in linea con marcatori di danno ossidativo a livello proteico e lipidico, nella prostata di ratto. L’esposizione di cellule IMR90 a VE ha evidenziato un effetto genotossico riportando un’aumentata frequenza dei micronuclei (MN). Il potenziale co-cancerogeno di VE è stato poi confermato dallo studio della trasformazione cellulare mediate l’uso di cellule BALB/c 3T3. Cellule pre-incubate con VE e successivamente esposte a benzo[a]pirene mostrano un significativo incremento della frequenza di trasformazione rispetto a quello senza della vitamina. Il presente studio dimostra come la VE possa, in determinate condizioni, agire come co-cancerogeno tramite un meccanismo CYP-dipendente, causando danno al DNA e promovendo la trasformazione cellulare.

As of January 2020, a new pandemic has spread from Wuhan and caused thousands of deaths worldwide. Several studies have observed a relationship between coronavirus disease (COVID-19) infection and the cardiovascular system with the appearance of myocardial damage, myocarditis, pericarditis, heart failure and various arrhythmic manifestations, as well as an increase in thromboembolic risk. Cardiovascular manifestations have been highlighted especially in older and more fragile patients and in those with multiple cardiovascular risk factors such as cancer, diabetes, obesity and hypertension. In this review, we will examine the cardiac involvement associated with SARS-CoV-2 infection, focusing on the pathophysiological mechanism underlying manifestations and their clinical implication, taking into account the main scientific papers published to date.

Cerebral plasticity is the ability of the central nervous system to reorganize itself in response to different injuries. The reshaping of functional areas is a crucial mechanism to compensate for damaged function. It is acknowledged that functional remodeling of cortical areas may occur also in glioma patients. Principal limits of previous investigations on cortical plasticity of motor and language functions included scarce reports of longitudinal evaluations and limited sample sizes. This systematic review is aimed at elucidating cortical brain plasticity for motor and language functions, in adult glioma patients, by means of preoperative and intraoperative mapping techniques. We systematically reviewed the literature for prospective studies, assessing cortical plasticity of motor and language functions in low-grade and high-grade gliomas. Eight longitudinal studies investigated cortical plasticity, evaluated by motor and language task-based functional MRI (fMRI), motor navigated transcranial magnetic stimulation (n-TMS), and intraoperative mapping with cortical direct electrocortical stimulation (DES) of language and motor function. Motor function reorganization appeared relatively limited and mostly characterized by intrahemispheric functional changes, including secondary motor cortices. On the other hand, a high level of functional reshaping was found for language function in DES studies. Occurrence of cortical functional reorganization of language function was described focusing on the intrahemispheric recruitment of perilesional areas. However, the association between these functional patterns and recovery of motor and language deficits still remains partially clear. A number of relevant methodological issues possibly affecting the finding generalization emerged, such as the complexity of plasticity outcome measures and the lack of large longitudinal studies. Future studies are required to further confirm these evidences on cortical plasticity in larger samples, combining both functional imaging and intraoperative mapping techniques in longitudinally evaluations.

E-cigarettes induce toxicological effects that can raise the cancer risk. The contribute of EPR radical probe technique Donatella Canistro1, Fabio Vivarelli1, Silvia Cirillo1, Andrea Sapone1, Moreno Paolini1, Paola Franchi2, Marco Lucarini2 1Department of Pharmacy and Biotechnology (University of Bologna, Via Irnerio 48, I-40126 Bologna, Italy) 2Department of Chemistry “G. Ciamician” (University of Bologna, Via San Giacomo 11, I-40126 Bologna, Italy) E-mail: paola.franchi@unibo.it Electronic cigarettes (e-cigs) are devices designed to deliver nicotine in a vaping solution rather than smoke and without tobacco combustion. Perceived as a safer alternative to conventional cigarettes, e-cigs are aggressively marketed as lifestyle-choice consumables, thanks to few restrictions and a lack of regulatory guidelines. Despite the burgeoning worldwide consumption of e-cigs, their safety remains largely unproven and it is unknown whether these devices cause in vivo toxicological effects that could contribute to cancer. Here we illustrate the contribute of EPR radical probe technique in a study where it was possible to demonstrate the co-mutagenic and cancer-initiating effects of e-cig vapour in a rat lung model. It was found that e-cig have a powerful booster effect on phase-I carcinogen-bioactivating enzymes, and increase oxygen free radical production and DNA oxidation. We are able to indirectly evaluate the content of reactive oxygen species (ROS) in lungs tissues of exposed rats, by using an appropriate hydroxylamine that in the presence of transient radical species gives rise to a persistent nitroxide radical. (see Scheme 1) Scheme 1 We found a significant increase of radical species production in samples of lungs tissues from exposed rats compared to samples from non-exposed animals. [1] Canistro, D.; Vivarelli, F.; Cirillo, S.; Babot Marquillas, C.; Buschini, A.; Lazzaretti, M.;Marchi, L.; Cardenia, V.; Rodriguez-Estrada, M.T.; Lodovici, M.; Cipriani, C.; Lorenzini, A.; Croco, E.; Marchionni, S.; Franchi, P.; Lucarini, M.; Longo, V.; Della Croce, C.M.; Vornoli, A.; Colacci, A.; Vaccari, M.; Sapone, A.; Paolini, M. SCIENTIFIC REPORTS. 2017, DOI:10.1038/s41598-017-02317-8 [2] Vivarelli, F.; Canistro, D.; Franchi, P.; Sapone, A.; Vornoli, A.; Della Croce, C.; Lucarini, M.; Paolini, M. Life Sciences, 2016, 145, 166-173. DOI:10.1016/j.lfs.2015.12.033 [3] Fabbri, R.; Sapone, A.; Paolini, M.; Vivarelli, F.; Franchi, P.; Lucarini, M.; Pasquinelli, G.; Vicenti, R.; Macciocca, M.; Venturoli, S.; Canistro, D. Hystology and Hystopatology, 2015, 30, 725-730 DOI: 10.14670/HH-30.725

E-CIGARETTES INDUCE TOXICOLOGICAL EFFECTS THAT CAN RAISE THE CANCER RISK. A FRAME FROM DRUG-METABOLISM AND ANTIOXIDANT HOMEOSTASIS. 1)Canistro D. 2)Vivarelli F. 3)Cirillo S. 4)Cardenia V. 5)Rodriguez-estrada MT. Dept of Pharmacy and Biotechnology, Unibo Electronic cigarettes (e-cigs) are devices designed to deliver nicotine in a vaping solution without tobacco combustion. Perceived as a safer alternative to conventional cigarettes, e-cigs are aggressively marketed as lifestyle-choice consumables, thanks to few restrictions and a lack of regulatory guidelines. Despite the burgeoning worldwide consumption of e-cigs, their safety remains largely unproven and it is unknown whether these devices cause in vivo toxicological effects that could contribute to cancer occurrence. In the present study, we investigated the co-mutagenic and cancer-initiating effects of e-cig vapour in a rat model. To explore whether e-cigs induce toxicological effects, such as those involving cytochrome P450 (CYP) changes, we analyzed the modulation of carcinogen metabolizingenzymes in the lung of rats exposed to e-cig vapour. We observed a significant increase in CYP1A1/2 (activating, for example, polychlorinated biphenyls, aromatic amines, dioxins and PAHs), CYP2B1/2 (activating olefins and halogenated hydrocarbons), 2C11 (activating nitrosamines and mycotoxins) and CYP3A (activating hexamethyl phosphoramide and nitrosamines) documented by the sharp rise in the corresponding probes. Conversely, we observed that the antioxidant enzymes catalase, DT-diaphorase and glutathione peroxidase and the conjugating phase II glutathione S-transferases, mainly involved in xenobiotic detoxification, were noticeable decreased, whereas UDP-glucuronyl-transferase was substantially unchanged. Extrapolated to humans, the corresponding boosted CYP-linked monooxygenases together with reduced activity of antioxidant and detoxifying machinery would predispose a subject to an enhanced cancer risk from the widely bioactivated e-cig vapour procarcinogens associated with an increased risk of lung cancer.

Development of microparticles for oral administration of the non-conventional radical scavenger IAC and testing in an inflammatory rat model 1)Cirillo S.. 2)Paolini M.. 3)Vivarelli F.. 4)Passerini N.. 5)Albertini B.. 6)Di sabatino M. 7)Corace G.. 8)Luppi B.. 9)Canistro D.. University of Bologna The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) is an innovative nonconventional radical scavenger used with success in several disease models, such as inflammation, neurological disorders, hepatitis and diabetes. To date, the main limit for the drug use is represented by the intraperitoneal (i.p.) route of administration used in the pharmacological treatments. In order to develop a delivery system that allowed both oral administration and the therapeutic efficacy, Solid Lipid Microparticles (SLMs) containing a theoretical 18% w/w of IAC have been produced. Recently, three formulations (A, B, C) have been tested at different dosages in an inflammation and pain rat model. Inflammatory model was induced by the use of an intraplantar injection of 100ml/paw of Freund's complete adjuvant (FCA). Administered per os at different dosages, IAC B (60% stearic acid-20% Compritol® HD5 ATO) was the most efficient formulation in reducing oedema and alleviating pain, compared to the gold standard Paracetamol. Since the anti-diabetic effects of the i.p. formulation of IAC was already demonstrated in vivo, we are now investigating the therapeutic efficacy of the selected (B) oral IAC formulation (SLMs) in streptozotocin-nicotinamide diabetic mice.

Effects of electronic cigarette vapors exposure on oxidative damage and antioxidant status. 1)Bigagli E. 2)Canistro D. 3)Paolini M. 4)Vivarelli F. 5)Cirillo S. 6)Lodovici M. 1)Neurofarba, University of florence, Florence, Italy 2)Farmacia e biotecnologie, University of bologna, Bologna, Italy 3)Farmacia e biotecnologie, University of bologna, Bologna, Italy 4)Farmacia e biotecnologie, University of bologna, Bologna, Italy 5)F Electronic cigarettes (e-cigs) are devices designed to deliver nicotine without burning tobacco and therefore, they are perceived as a safer alternative to the conventional cigarettes. However, because of the high temperature reached by e-cig solutions (> 200 C°) many toxic substances, including polycyclic aromatic hydrocarbons, formaldehyde, nitrosamines, metals and carbonyls can be generated. Very few in vivo animal studies have been conducted so far, most of them based on short-term e-cig exposure. The aim of this study was therefore to evaluate the influence of e-cigs on oxidative stress related parameters, classical markers associated to conventional cigarette toxicity. Male Sprague Dawley rats (8 weeks of age), were housed in an inhalation chamber and exposed either to e- cig vapors (1 mL/day of e-liquid containing 18 mg/mL of nicotine) or to a saline solution. One cycle of treatment consisted in 17 sec puff, 6 sec on, 5 sec off, 6 sec on, followed by 20 minutes stop. e-cigs voltage was set at 5.5. Animals were submitted to 11 cycles/ day for 5 consecutive days/week, for 4 consecutive weeks. At sacrifice, liver, kidneys, lungs, bladder and plasma were collected for the analysis of protein (carbonyl residues) and DNA oxidative damage (8-hydroxy-2’-deoxyguanosine (8-OHdG)) and of the total antioxidant power (FRAP assay). At lung level, we found that FRAP values of rats exposed to e-cigs vapors were markedly reduced compared to controls. A similar trend was observed in the plasma, even if the statistical significance was not reached. Plasma FRAP levels and carbonyl residues were inversely correlated in e-cig exposed rats but not in controls. We also found that 8-OHdG markedly increased in the lung of e-cig vapor exposed rats compared to controls. An inverse correlation between FRAP levels and 8-OHdG in lung tissue from exposed animals was also observed. These results demonstrate that e-cig vapor causes DNA oxidative damage and impairs antioxidant defenses in rats; given that these toxicological outcomes are typically induced by conventional cigarettes smoking, further investigations to better identify harmful e-cig effects especially in the long term, are of paramount importance.

Cancer of the larynx in the intermediate/advanced stage still presents a major challenge in terms of controlling the disease and preserving the organ. Supratracheal partial laryngectomy (STPL) has been described as a function-sparing surgical procedure for laryngeal cancer with sub-glottic extension. The aim of the present multi-institutional study was to focus on the indications and contraindications, both local and general, for this type of surgery based on the long-term oncological and functional results. We analysed the clinical outcomes of 142 patients with laryngeal cancer staged pT2-pT4a who underwent STPL. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS) and loco-regional control (LRC) rates were: glottic pT2 [71.4%, 95.2%, 76.0%, 76.0%], glottic-transglottic pT3 [85.3%, 91.1%, 86.4%, 88.7%], and pT4a [73.2%, 88.1%, 52.7%, 60.7%], respectively. DFS and LRC prevalences at 5 years were greatly affected by pT4a staging. Five-year laryngeal function preservation (LFP) and laryngectomy free survival (LFS) were: glottic pT2 [90.9%, 95.2%], glottic-transglottic pT3 [84.4%, 93.1%], and pT4a [63.7%, 75.5%], respectively, being affected by pT staging and age 65 ≥ years (LFP 54.1%). As a result of Type III open horizontal partial laryngectomies (OPHLs) (supratracheal laryngectomies), the typical subsites of local failure inside the larynx were the mucosa at the passage between the remnant larynx and trachea, the mucosa at the level of the posterior commissure and the contralateral cricoarytenoid unit as well as outside the larynx at the level of the outer surface of the remnant larynx. For patients with glottic or transglottic tumours and with sub-glottic extension, the choice of STPL can be considered to be effective, not only in prognostic terms, but also in terms of functional results.Il cancro della laringe in fase intermedio / avanzata rappresenta ancora una grande sfida in termini di controllo della malattia e di preservazione d'organo. La laringectomia parziale sopratracheale (STPL) è stata descritta come procedura chirurgica di function-sparing per il cancro della laringe con estensione sub-glottica. Lo scopo del presente studio multi-istituzionale è di concentrarsi sulle indicazioni e controindicazioni, sia locali che generali, per questo tipo di chirurgia sulla base dei risultati oncologici e funzionali a lungo termine. Abbiamo analizzato i risultati clinici di 142 pazienti con cancro della laringe in stadio pT2-pT4a sottoposti a STPL. A cinque anni i tassi di sopravvivenza globale (OS), di sopravvivenza malattia specifica (DSS), di sopravvivenza libera da malattia (DFS) e di controllo loco-regionale (LRC) sono risultati rispettivamente: pT2 glottici [71,4%, 95,2%, 76,0%, 76,0%] , pT3 glottici-transglottici [85,3%, 91,1%, 86,4%, 88,7%], e pT4a [73,2%, 88,1%, 52,7%, 60,7%]. La DFS ed il LRC a 5 anni sono risultati fortemente influenzati dallo stadio pT4a. A cinque anni i tassi di conservazione della funzione laringea (LFP) e la sopravvivenza libera da laringectomia (LFS) sono risultati: pT2 glottici [90,9%, 95,2%], pT3 glottici-transglottici [84,4%, 93,1%] e pT4a [63,7%, 75,5%], risultando negativamente influenzati dal pT staging e dall'età di 65 ≥ anni (LFP 54,1%). A seguito di laringectomia parziale sopratracheale le sedi tipiche di recidiva sono risultate all'interno della laringe la mucosa al passaggio fra laringe residua e trachea , la mucosa a livello della commissura posteriore, l'unità cricoaritenoidea controlaterale e all'esterno la superficie esterna della laringe residua. Per i casi di tumore glottico con estensione subglottica o di tumore con importante estensione transglottica, la scelta di una STPL può essere considerata efficace, non solo in termini prognostici, ma anche in termini di risultati funzionali.