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In the context of the global COVID-19 pandemic, companies and institutions all over the world are trying to find the best ways to reorganize their activity, minimizing the contagion risk among their employees, so as to protect their health and prevent internal SARS-COV-2 outbreaks. The recent development of new communication technologies, such as smartphones and tablets, has paved the way for the development and implementation of different applications. Starting with the above issues, in this study, we wanted to investigate the efficacy of iAudiometry application developed by our research team for the detection of deficits in the auditory system. Furthermore, we analyzed the precision in detecting ambient Sound Pressure Levels between 3 different types of headphones. To this aim we divided the study and development process into four main phases: the feasibility study; the development of a signal generation algorithm, calibration and evaluation of the ambient Sound Pressure Level (SPL) on different types of headphones, and; a comparative study between conventional audiometry and an app with related headphones. Finally, this study allowed us to differentiate the headphones tested into 3 different types: headphones suitable for professional screening; Bluetooth headphones suitable for professional screening, and; headphones with slight but statistically significant differences, not suitable for professional screening. Our App is able to easily reproduce a reliable audiometric screening, limiting the contact between patient and examiner.

In this study we explored the effect and the biological action of synthesized benzamido derivatives bearing the (1S,2S)-2-phenyl-cyclopropane-1-carboxamido, 1,1'-biphen-2-carboxamido and 1,1'-biphen-4-carboxamido moieties on K562, a human leukemia cell line. Among the synthesized compounds a particular antiproliferative action was observed with the benzamido derivative bearing the 2-1,1'-biphenyl moiety with the substitution at the 5 position of the benzamido moiety with iodine. This compound showed cytotoxic effects in K562 leukemic cells at nanomolar concentrations and was, therefore, chosen as compound to explore its mode of action. Our analyses provided evidence that this benzamido derivative induced a reduction in cell number and volume with the appearance of a shrunken cytoplasm at 24h, followed by a widespread cell fragmentation at 48h. As demonstrated by flow cytometry analyses, the effect was dose- and time-dependent, causing a G2/M cell cycle arrest in the first phase of treatment (24h), followed by an apoptotic death at 48h (IC50 0.5 μM ). The elucidation of the underlying mechanism also disclosed that DNA arrest in G2/M phase of cell cycle was consequent to DNA lesions, since an increase in phospho-ATM and yH2AX, two known markers of DNA repair response system, was observed. Prolonging the time of treatment, the effects, which were observed only in leukaemic cells but not in normal bronchial epithelial cells, were accompanied by ROS production, JNK phosphorylation and induction of a caspase-dependent apoptosis.

The effects of alcohol have been widely studied during the past century as alcohol abuse is a major health problem in Western society. In the last years, a growing body of evidence indicates that acetaldehyde, the first oxidation product of ethanol, is one of the mediators of peripheral and central effects of ethanol. Indeed, acetaldehyde has been recently taken into account as the mediator of the rewarding properties of alcohol. The role of acetaldehyde in ethanol-related properties has been proved by enzymatic manipulation studies in which the inactivation of acetaldehyde potentially synthesized in the brain produces the same results as blocking the formation of acetaldehyde by inhibiting brain catalase activity. Moreover, electrophysiological and pharmacological analyses showed that acetaldehyde is able to stimulate dopamine release in the nucleus accumbens through enhancement of firing rate, spikes/burst, and burst firing of ventral tegmental neurons. Thus, the aim of this review is to summarize latest results on the role of acetaldehyde as the mediator of ethanol-central effects.

Le cinnammido benzammidi rappresentano una classe di sostanze biologicamente attive di grande interesse farmaceutico. Nonostante siano state descritte per svariate attività biologiche, nessun dato è stato riportato sulla loro attivita antitumorale. Inizialmente una serie di 2-cinammidobenzammidi variamente sostituite sono state sintetizzate e valutate per la loro attività antiproliferativa. Partendo dal derivato risultato più attivo, il 2-cinnammido-5-iodobenzammide, che ha mostrato una percentuale di inibizione della crescita sulle K562 del 74% a 10μM, sono stati sintetizzati una serie di derivati al fine di approfondirne la SAR.I composti così ottenuti sono risultati attivi nei confronti di numerose linee cellulari tumorali a concentrazioni micromolari e submicromololari inducendo un blocco del ciclo cellulare delle K562 in fase G2M. Inoltre i derivati sintetizzati sono in grado di indurre apoptosi nelle cellule HEP G2.

3,4-diphenylisoxazolo[3,4-d]pyridazin-7(6H)-one analogs were synthesized and tested for the antiproliferative activity. Study on the cell cycle alteration and on some cellular target (ATM, procaspase-2 proteins and H2AX histone) demonstrate the increase of the cell population in S phase and to induce cellular death by apoptosis by DNA damage with double strand breaks.

The effects of alcohol have been widely studied during the past century, corroborating the idea that this tiny chemical compound acts throughout most of our neurotransmitter systems since it is capable of inducing addictive behaviour. Two of the most serious problems of alcohol addiction are craving and relapse; several studies have demonstrated that relapse is related to the anxious state which occurs during withdrawal, and it has been proved that this behavioural modifications results from an alteration of the dopaminergic and serotonergic systems. An important role in the neurobiology of alcohol addiction is played by acetaldehyde (ACD), ethanol first metabolite. Our recent studies indeed, have demonstrated that ACD itself is able to induce CRH release from hypothalamic explants, underlying the central role played by ACD in alcohol-induced modifications of the HPA axis. Moreover, for the first time, this group has shown that ACD is able to induce and maintain an operant drinking behaviour after repeated abstinence periods, and in the presence of a conflict situation in rats, mimicking the same characteristics as alcohol. ACD is produced either peripherally or within the brain by alcohol dehydrogenase and catalase, respectively. Studies assert that the highest concentrations of catalase in the brain are mainly located in aminergic neurons suggesting that ACD could take part in alcohol action in those circuitries. Further investigations are then necessary to fully understand the molecular mechanisms underlying the neurochemical and behavioural modifications induced by ACD, as a mediator of alcohol activity in the brain., peer-reviewed

Respiratory tract infections are the most common diseases in childhood. The respiratory tract, widely branched system of ducts, is particularly exposed to the action of microorganisms transmitted by air from here the high frequency of infections they face especially in the first years of life. It is usual distinguish: upper respiratory tract infections (URTI) and lower respiratory tract infections (LRTI). In particular, in infections of the upper airways, the inflammatory process, result of the interaction between microbes and the immune response, can be localized to the mucosa of the nose or sinuses (common cold and sinusitis), or the pharynx or larynx (pharyngotonsillitis and laryngitis) and it has predominantly a viral etiology although occasionally it may be followed by bacterial complications such as otitis media. The aim of the following article is the description of these different clinical pictures, highlighting the clinical and epidemiological features and current management guidelines.

Introduction: To examine the putative association between Sleep-Disordered breathing and hearing disorders Material and methods: 120 Sicilian subjects ranging from 14 to 85 years of age who were divided in 46 cases suffering from tinnitus (G1 group) and 74 controls (G2 group) were evaluated through STOP BANG screening questionnaire and Four-Variable Screening Tool; after Data collecting each subject underwent Audiological assessment by multi-frequency audiometry (PTA) and Transient-evoked otoacoustic emissions (TEOAE-diagnostic) for each ear. Results: Cases showed: PTA significantly severe than the control group (58.70% vs. 16.89% hearing loss; P

Early exposure to stressful stimuli is crucial for developing varied behavioural patterns in adulthood such as anxiety, cognitive dysfunction and abuse disorders. The alteration of the hypothalamic–pituitary–adrenal (HPA) axis represents the neurobiological substrate responsible of the behavioural consequences of prenatal stress (PS). Indeed, prenatal manipulation of the HPA axis impacts on cognitive performance of the adult offspring, but also on vulnerability to alcohol consumption. Prenatal acute, moderate restraint stress has proved to facilitate HPA axis development of the offspring, since maternal corticosterone secretion leads to the reduction of anxiogenic behaviour and an improvement in the ability to cope with stress, increasing both the rate of learning and long-term potentiation, but also gestational stress blunts initial alcohol-induced HPA axis activation. In our recent study, moderate alcohol intake proved to reduce emotionality and facilitate the adaptive responses to stress, enhancing behavioural flexibility. Based upon these findings, we aimed at assessing the impact of a single, intense prenatal stress on exposure to alcohol preference and on the effects exerted by ethanol on behavioural reactivity, anxiety-like behaviour and spatial learning in adult male Wistar rats.

In un precedente lavoro abbiamo mostrato i risultati relativi alla sintesi ed all’attività biologica del CF3-TZP 1[1] (Figura 1). Le attività antiproliferativa e apoptotica del composto 1 sono state testate su differenti linee cellulari, HL60 sensibili, HL60-R (MDR), K562 e K562-R (resistenti al Gleevec®), mostrando un profilo di attività biologica similare sulle cellule sensibili e resistenti nel range di 21-40 µM per l’IC50 e 36-62 µM per l’AC50. L’analisi citofluorimetrica sulle K562 sensibili ha indicato che il composto 1 determina un arresto dose-dipendente del ciclo cellulare in fase G0-G1 nelle prime 24 h di trattamento, mentre nelle successive 24 h si è notato una riduzione del picco G0-G1 ed un incremento del picco apoptotico subG0-G1. Gli incoraggianti risultati biologici ci hanno spinto a continuare gli studi su questa tipologia di molecole sintetizzando l’isostero 2 (Figura 1) attraverso una lunga via di sintesi (15 steps). Attualmente, sono in corso i saggi biologici per valutare le attività antiproliferativa e apoptotica. Bibliografia 1 Maggio, B.; et al, Eur. J. Med. Chem., 2008, 43, 120.

I chinazolinoni sono composti eterociclici azotati che, insieme alle chinazoline, rappresentano degli importanti farmacofori in possesso di un ampio spettro di proprietà biologiche tra cui quella antitumorale. Recentemente sono stati riportati in letteratura dei derivati 4-chinazolinonici in grado di inibire in vitro l’enzima diidrofolato reduttasi (DHFR) con IC50 comprese tra 0.4 e 1.0 µM [1]. Allo scopo di progettare la sintesi di nuovi potenziali inibitori della DHFR, è stato condotto uno studio di modellistica molecolare considerando tale enzima come biotarget. Tale studio ha portato alla selezione di 42 nuovi derivati 4-chinazolinonici (Figura 1). Attualmente, sono stati sintetizzati 20 dei 42 nuovi derivati 4-chinazolinonici, che sono stati saggiati preliminarmente sulla linea cellulare K562. Il derivato più attivo ha mostrato una IC50 di 18 µM. Sono in corso saggi enzimatici per valutare in vitro l’inibizione dell’enzima DHFR. Bibliografia 1 Al-Omary F.A.M.; et al, Bioorganic & Medicinal Chemistry, 2010, 18, 2849.

La Sortasi A è un enzima di membrana responsabile dell’ancoraggio delle proteine di superficie sulla parete cellulare dei batteri Gram-positivi. Essa è considerata un interessante obiettivo per lo sviluppo di nuovi farmaci anti-infettivi che mirino ad interferire con importanti meccanismi di virulenza Gram-positivi. In un precedente lavoro abbiamo indagato sull’attività antistafilococcica e antibiofilm di alcune Pirrolomicine naturali e sintetiche, composti pirrolici polialogenati attivi su patogeni Gram-positivi, alle concentrazioni di 1.5 e 0.045 µg/mL. I risultati biologici hanno mostrato percentuali di inibizione di biofilm comprese tra 50-80% [1]. Allo scopo di indagare sul loro meccanismo d’azione sono stati condotti studi di modellistica molecolare e saggi di inibizione in vitro sull’enzima Sortasi A (Figura 1). I risultati ottenuti indicano che la Sortasi A potrebbe essere il bersaglio sul quale le Pirrolomicine agiscono, con IC50 comprese tra 130-250 µM, nell’inibizione della formazione di biofilm. Bibliografia 1 Schillaci, D.; et al, Biofouling, 2010, 26, 433.

Tinnitus is a frequent symptom in audiological clinical practice characterized by an abnormal noise perceived in one or both ears or in the head, in which a patient has a conscious hearing percept in absence of external sound. Tinnitus might be caused by a homeostatic response of central dorsal cochlear nucleus auditory neurons that makes them hyperactive in compensation to auditory input loss. One hypothesis suggests that tinnitus is a sensory form of epilepsy that involves the cochlear nucleus and the inferior colliculus, which display impairment in the electrical activity in the auditory system. This alteration determines a synaptic plasticity in the dorsal cochlear nucleus that becomes a target for pharmacological compounds able to treat tinnitus. There is no effective drug treatment for tinnitus, but different studies propose the use of cannabinoid receptors agonist for their anti-epileptic activity, although their practical effects are still unclear. In this review, we want to analyze the emerging pharmacological approaches of cannabinoid receptor agonists to the therapy of tinnitus.

Background: Insomnia is the perception of inadequate, insufficient or non-restorative sleep. Of all sleep-related disorders, insomnia is the most common. It is important to remember that the sleep–wake cycle also plays a central role in the genesis of anxiety and depression. The aim of our study is to evaluate the association between sleep disturbances and anxiety and depression in a group of workers of both sexes who perform night shift work. Methods: Information on sleep disorders was collected by administering the Insomnia Severity Index (ISI) questionnaire. Statistical analysis was conducted using the Chi-square test to assess whether there were any differences between sex for those who were healthy or who were diagnosed with psychiatric disorders. Results: The results showed that there was a good percentage of subjects with insomnia problems, impairing normal daily activities and promoting the onset of fatigue, daytime sleepiness, cognitive performance deficits and mood disorders. Conclusion: We highlighted how anxious and depressive anxiety disorders are more pronounced in people who suffer from altered sleep–wake rhythms. Further research in this direction could prove to be fundamental for understanding the genesis of the onset of other disorders as well.

Almost two years after the beginning of the SARS-CoV-2 pandemic, the knowledge of which in the infectious and therapeutic spheres is constantly evolving, attention paid to the medicolegal aspects linked to this emergency phenomenon has mainly focused on the liability implications falling on healthcare personnel. With regard to the medicolegal assessment of the outcomes of COVID-19 illness, although it is a procedure that is commonly used, and although references in the assessment tables in force have been adhered to, a specific assessment protocol has not been standardized that takes into account, from an objective point of view, the degree of severity of the long-term residual outcomes and their impact on the social and working lives of subjects. This shortcoming appears to be attributable to the immediate need to categorize the results of COVID-19, but, in our opinion, it deserves an in-depth study and protocols to enable evaluation committees to draw up an assessment as precisely as possible and that is free of gaps, which could be the subject of legal disputes. The aim of the present work, in light of a worldwide problem, is to arrive at specific and univocal evaluation criteria for COVID-19 disease outcomes, applicable in different operational contexts of reemployment.

The sleep-wake cycle plays a fundamental role in maintaining the physiological balance of our body. Its alteration favours the genesis of several organic alterations and diseases including sleep disorders and the consumption of several substances of abuse. It has been reported that the work activity, especially that carried out during the night, is able to influence the sleep-wake cycle, promoting the development of insomnia, which, in turn, would subject the worker to a stressful condition such as to encourage adverse behaviour such as the use/abuse of psychotropic substances. Based on the above premises, the aim of our research was to evaluate, in night workers: (i) the pattern of consumption of alcoholic beverages; (ii) the presence of insomnia; and (iii) the possible correlation between alcohol consumption and insomnia disorder. We used the AUDIT-C test (the abbreviated version of the Alcohol Use Disorders Identification Test) and the Insomnia Severity Index to assess alcohol consumption and insomnia disorder, respectively. All questionnaires were completed by workers of both sexes belonging to different types of work activities, exclusively day or night. The results of our research show a higher propensity of night workers to consume alcoholic beverages than those who work during daytime hours, often in binge-drinking mode. In addition, an increase in the amount of alcohol consumed was found to be related to insomnia disorder, especially in night workers. This study provides further awareness of the importance of the negative impact of alcohol consumption on sleep quality in night workers.

Vertigo is not itself a disease, but rather a symptom of various syndromes and disorders that jeopardize balance function, which is essential for daily activities. It is an abnormal sensation of motion that usually occurs in the absence of motion, or when a motion is sensed inaccurately. Due to the complexity of the etiopathogenesis of vertigo, many pharmacological treatments have been tested for efficacy on vertigo. Among these drugs, cinnarizine, usually given together with dimenhydrinate, appears to be the first-line pharmacotherapy for the management of vertigo and inner ear disorders. Based on these considerations, the present non-interventional study aimed to investigate the clinical efficacy and tolerability of a fixed combination of cinnarizine (20 mg) and dimenhydrinate (40 mg) in patients suffering from vertigo-related symptoms. To this end, we enrolled 120 adults—70 males, and 50 females—with an average age of 64 years. Before beginning pharmacological treatment, all patients were screened for the intensity of vertigo, dizziness, and concomitant symptoms through the Visual Scale of Dizziness Disorders and Dizziness Handicap Inventory scales. At the end of the anamnestic evaluation, patients received the fixed-dose combination of cinnarizine (20 mg) plus dimenhydrinate (40 mg) 3 times daily, for 60 days. The results of this study provide further insight regarding the efficacy of the fixed combination when used to reduce symptoms of vestibular vertigo of central and/or peripheral origin, after both the 15- and 60-day therapies. Independent of the type of vertigo, the fixed combination was able to reduce dizziness- and vertigo-associated symptoms in more than 75% of all patients treated, starting from 15 days of therapy, and improving 60 days after starting the therapy. Interestingly, we also found differences between male and female patients in the framework of the pharmacological effects of therapy. This study provides further details concerning the therapeutic efficacy of the fixed combination of cinnarizine and dimenhydrinate, and also focuses attention on the possibility that these drugs could act in a gender-specific manner, paving the way for further research.

Acute or chronic administration of guanosine (GUO) induces anxiolytic-like effects, for which the adenosine (ADO) system involvement has been postulated yet without a direct experimental evidence. Thus, we aimed to investigate whether adenosine receptors (ARs) are involved in the GUO-mediated anxiolytic-like effect, evaluated by three anxiety-related paradigms in rats. First, we confirmed that acute treatment with GUO exerts an anxiolytic-like effect. Subsequently, we investigated the effects of pretreatment with ADO or A1R (CPA, CCPA) or A2AR (CGS21680) agonists 10 min prior to GUO on a GUO-induced anxiolytic-like effect. All the combined treatments blocked the GUO anxiolytic-like effect, whereas when administered alone, each compound was ineffective as compared to the control group. Interestingly, the pretreatment with nonselective antagonist caffeine or selective A1R (DPCPX) or A2AR (ZM241385) antagonists did not modify the GUO-induced anxiolytic-like effect. Finally, binding assay performed in hippocampal membranes showed that [3H]GUO binding became saturable at 100&ndash, 300 nM, suggesting the existence of a putative GUO binding site. In competition experiments, ADO showed a potency order similar to GUO in displacing [3H]GUO binding, whereas AR selective agonists, CPA and CGS21680, partially displaced [3H]GUO binding, but the sum of the two effects was able to displace [3H]GUO binding to the same extent of ADO alone. Overall, our results strengthen previous data supporting GUO-mediated anxiolytic-like effects, add new evidence that these effects are blocked by A1R and A2AR agonists and pave, although they do not elucidate the mechanism of GUO and ADO receptor interaction, for a better characterization of GUO binding sites in ARs.

Introduction: SARS-CoV-2, identified in Wuhan, China, for the first time in December 2019, is a new viral strain, which has not been previously identified in humans; it can be transmitted both by air and via direct and indirect contact; however, the most frequent way it spreads is via droplets. Like the other viruses belonging to the same family of coronaviruses, it can cause from mild flu-like symptoms, such as cold, sore throat, cough and fever, to more severe ones such as pneumonia and breathing difficulties, and it can even lead to death. Since no effective specific drug therapy has been found yet, nor any vaccine capable of limiting the spread of this pathogen, it is important for ways of preventing the spread of this infection to be established. Methods: the purpose of our research was to provide a protocol to prevent the spread of SARS-CoV-2 infection in light of the limited information related to this coronavirus. In detail, we analysed and searched targeted evidence-based guidelines issued in the various countries affected by this epidemic up till now. In addition, we analyzed the recommendations for the prevention and control of other epidemics caused by other pathogens belonging to the same family of coronaviruses or others that present the same mechanisms of transmission. Discussion: general organizational measures regarding the containment and management of the epidemiological emergency of COVID-19 have been imposed by the competent authorities for an adequate and proportionate management of the evolution of the epidemiological situation. The prevention and protection organizational measures therefore aim to minimize the probability of being exposed to SARS-CoV-2. For this purpose, measures must also be taken at work to avoid new infections or even the spread of the virus where it has already been present. Furthermore, environmental measures are aimed at reducing the risk of transmission of SARS-CoV-2 to individuals through contact with infected subjects, objects, equipment, or contaminated environmental surfaces. Conclusion: protective devices must be used whenever there is potentially close contact with a suspect case, especially when the potentially infected person does not wear a surgical mask that could reduce the spread of viruses in the environment. By adopting this specific prevention and protection measures recommended in the workplace, it will be possible to help overcome this COVID-19 pandemic.

Work-related stress can induce a break in homeostasis by placing demands on the body that are met by the activation of two different systems, the hypothalamic&ndash, pituitary&ndash, adrenal axis and the sympathetic nervous system. Night-shift work alters the body&rsquo, s exposure to the natural light&ndash, dark schedule and disrupts circadian (daily) rhythms. The greatest effect of night-shift work is the disruption of circadian rhythms. The impact that these disruptions may have on the pathogenesis of many diseases, including cancer, is unknown. This study aims to discover the relationship among three different job activities of security guards and their stress-related responses by evaluating salivary cortisol levels and blood pressure. Methods: Ninety security guards, including night-time workers and night-time and daily-shift workers, were recruited for this study. Each security guard provided two saliva samples before and after three scheduled time points: (i) at 22:00, (ii) at 06:30, and (iii) at 14:00. Results: The results of the study showed a significant alteration in cortisol levels. Night-time shift cortisol levels significantly increased before and after the work shifts. A physiological prevalence of the vagal tone on the cardiocirculatory activity was found during night-shift work. Conclusions: This study indicates that cortisol levels and blood pressure are sensitive markers of biological responses to severe work stress. Shift-change consequences may occur at the end of the night shift when there is a significant increase in the cortisol level and a significant variation in cardiovascular parameters.

While a lot is known about the mechanisms promoting aversive learning, the impact of rewarding factors on memory has received comparatively less attention. This research investigates reward-related explicit memory in male rats, by taking advantage of the emotional-object recognition test. This is based on the prior association, during conditioned learning, between a rewarding experience (the encounter with a receptive female rat) and an object; afterwards rat discrimination and recognition of the â emotional objectâ is recorded in the presence of a novel object, as a measure of positive limbic memory formation. Since endocannabinoids are critical for processing reward and motivation, the consequences of the stimulation of cannabinoid signalling are also assessed by the administration of WIN 55,212-2 at pre- and post-conditioning time. Our results show that rats encode the association between object and rewarding experience, form positive limbic memory of the emotional object, and retrieve this information in the face of novelty. Stimulation of the cannabinoid system at pre-conditioning time is able to strengthen reward-related explicit memory in the presence of novelty, whereas post-conditioning activation increases approach behaviour to novel stimuli. The assessment of limbic memory by the emotional-object recognition test can help unveiling the addictive and confounding properties of psychotropic drugs.

Although binge drinking is on the rise in women of reproductive age and during pregnancy, the consequences in the offspring, in particular the inheritance of alcohol-related mood disturbances and alcohol abuse vulnerability, are still poorly investigated. In this study, we modeled both Habitual- and Binge Alcohol Drinking (HAD and BAD) in female rats by employing a two-bottle choice paradigm, with 20% alcohol and water. The exposure started 12 weeks before pregnancy and continued during gestation and lactation. The consequences induced by the two alcohol drinking patterns in female rats were assessed before conception in terms of behavioral reactivity, anxiety- and depressive-like behavior. Afterwards, from adolescence to young-adulthood, male offspring was assessed for behavioral phenotype and alcohol abuse vulnerability. At pre-conceptional time BAD female rats showed higher mean alcohol intake and preference than HAD group; differences in drinking trajectories were attenuated during pregnancy and lactation. Pre-conceptional BAD induced a prevalent depressive/anhedonic-like behavior in female rats, rather than an increase in anxiety-like behavior, as observed in HAD rats. In the adolescent offspring, peri-gestational BAD did not affect behavioral reactivity in the open field and anxiety-like behavior in the elevated plus maze. Rather, BAD dams offspring displayed higher despair-behavior and lower social interaction with respect to control- and HAD dams progeny. Notably, only binge drinking exposure increased offspring vulnerability to alcohol abuse and relapse following forced abstinence. This is the first report showing that binge-like alcohol consumption from pre-conceptional until weaning induces relevant consequences in the affective phenotype of both the mothers and the offspring, and that such effects include heightened alcohol abuse vulnerability in the offspring. These findings highlight the need for more incisive public education campaigns about detrimental consequences of peri-gestational alcohol exposure.

Increasing evidence has focusesed on the endocannabinoid system as a relevant player in the induction of aberrant synaptic plasticity and related addictive phenotype following chronic excessive alcohol drinking. In addition, the endocannabinoid system is implicated in the pathogenesis of alcoholic liver disease. Interestingly, whereas the involvement of CB1 receptors in alcohol rewarding properties is established, the central and peripheral action of CB2 signalling is still to be elucidated. This review aims at giving the input to deepen knowledge on the role of the endocannabinoid system, highlighting the advancing evidence that suggests that CB1 and CB2 receptors may play opposite roles in the regulation of both the reinforcing properties of alcohol in the brain and the mechanisms responsible for cell injury and inflammation in the hepatic tissue. The manipulation of the endocannabinoid system could represent a bi-faceted strategy to counteract alcohol-related dysfunction in central transmission and liver structural and functional disarrangement.

Based on the encouraging results found for 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 7 previously tested by us, as well as the consideration that heterocycle fused tetrazepinones bearing the 2-chloroethyl substituent show a better cytotoxic profile than temozolomide and mitozolomide against human cancer cell lines which express the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), in this paper we report the multistep synthesis and the biological study of 3-(2-cloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 10. Like compound 7, it was active on P-glycoprotein expressing cells (MDR) HL60 and on K562 cell line that are resistant to apoptosis induced by different stimuli, showing GI50 values of 14 and 18 µM respectively. As an antiproliferative agent against the above cells compound 10 was about 2.2 times more active than compound 7. Compound 10 was also tested against WiDR cells which are overexpressing the DNA repair protein MGMT, showing a GI50 value of 2.3 µM. Finally, concerning the effect on cell cycle we observed an evident difference between compounds 7 and 10. In fact, compound 7 induces a block of cell cycle in G0-G1, therefore acting as phase-specific drug, in contrast, compound 10 is a not phase-specific agent. Both the compounds are able to increase the apoptotic sub G0-G1 peak of cell cycle.

Acetaldehyde contributes to alcohol’s psychoactive effects through its own rewarding properties. Recent studies shed light on the behavioral correlates of acetaldehyde administration and the possible interactions with key neurotransmitters for motivation, reward and stress-related response, such as dopamine and endocannabinoids. This mini review critically examines acetaldehyde psychoactive properties, focusing on behavioral investigations able to unveil acetaldehyde motivational effects and their pharmacological modulation in vivo. Similarly to alcohol, rats spontaneously drink acetaldehyde, whose presence is detected in the brain following chronic self-administration paradigm. Acetaldehyde motivational properties are demonstrated by operant paradigms tailored to model several drug-related behaviors, such as induction and maintenance of operant self-administration, extinction, relapse and punishment resistance. Acetaldehyde-related addictive-like behaviors are sensitive to pharmacological manipulations of dopamine and endocannabinoid signaling. Interestingly, the acetaldehyde-dopamine-endocannabinoids relationship also contributes to neuroplastic alterations of the NPYergic system, a stress-related peptide critically involved in alcohol abuse. The understanding of the menage-a-trois among acetaldehyde, reward- and stress-related circuits holds promising potential for the development of novel pharmacological approaches aimed at reducing alcohol abuse.

Several experimental and clinical studies have shown that a variety of ototoxic agents (such as drugs, industrial chemicals and noise) can cause sensorineural hearing loss. The most common ototoxic drugs used in clinical practice include: aminoglycoside and macrolide antibiotics, quinoline anti-malarials, platinum analog antineoplastics, loop diuretics, and acetylsalicylic acid. Among chemical agents with potential ototoxic properties are: organic solvents, heavy metals, organotins, nitriles, asphyxiants, and pesticides/herbicides. Acoustic exposure to high intensity and/or prolonged noise can also cause permanent threshold shifts in auditory perception. Ototoxic agents can influence auditory function by different mechanisms: RO S overload, inhibition of mitochondrial protein synthesis, DNA/RNA damage, activation of the apoptotic pathways, excessive calcium influx, increase of proinflammatory cytokines, interference with fluid and electrolyte balance of the endolymph, atrophy of the stria vascularis, changes in blood-labyrinth barrier and overstimulation of the stereocilia of the ear cells. Since noise exposure and many drugs or chemical compounds frequently share the same ototoxic mechanisms, this may explain why hearing loss can be potentiated by combined exposure to these agents. However, a great variability in the individual’s response to a given xenobiotic exists and depends on a complex interplay between endogenous and exogenous factors.

Rationale: In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. Objectives: Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. Methods: The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2mg/kg Oxo, and unstressed group treated with Oxo. After 21days of CRS, the groups were treated for 10days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels. Results: Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex Conclusions: The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex.

Background: Alcohol consumption during pregnancy and lactation induces detrimental consequences, that are not limited to the direct in utero effects of the drug on fetuses, but extend to maternal care. However, the occurrence and severity of alcohol toxicity are related to the drinking pattern and the time of exposure. The present study investigated in female rats long-term alcohol drinking trajectories, by a continuous and intermittent free-choice paradigm, during pre-gestational time, pregnancy, and lactation; moreover, the consequences of long-term alcohol consumption on the response to natural reward and maternal behavior were evaluated. Methods: Virgin female rats were exposed to home-cage two-bottle continuous- or intermittent “alcohol (20% v/v) vs. water” choice regimen along 12 weeks and throughout pregnancy and lactation. Animals were tested for saccharin preference, and maternal behavior was assessed by recording dams' undisturbed spontaneous home-cage behavior in the presence of their offspring. Results: Our results show that the intermittent alcohol drinking-pattern induced an escalation in alcohol intake during pre-gestational time and lactation more than the continuous access, while a reduction in alcohol consumption was observed during pregnancy, contrarily to the drinking trajectories of the continuous access-exposed rats. Long-term voluntary alcohol intake induced a decreased saccharin preference in virgin female rats and a significant reduction in maternal care, with respect to control dams, although the intermittent drinking produced a greater impairment than the continuous-access paradigm. Conclusion: The present data indicate that both alcohol-drinking patterns are associated to modifications in the drinking trajectories of female rats, in pre-gestational time, during pregnancy and lactation. Moreover, long-lasting alcohol intake can affect sensitivity to natural rewarding stimuli and maternal behavior and sensitivity to natural rewarding stimuli in a pattern–related manner. This study underlies the importance of modeling human alcohol habit and its consequences on the mother-infant dyad, in order to prevent detrimental effects on offspring development and maturation.

A FRET-based random screening assay was used to generate hit compounds as sortase A inhibitors that allowed us to identify ethyl 3-oxo-2-(2-phenylhydrazinylidene)butanoate as an example of a new class of sortase A inhibitors. Other analogues were generated by changing the ethoxycarbonyl function for a carboxy, cyano or amide group, or introducing substituents in the phenyl ring of the ester and acid derivatives. The most active derivative found was 3-oxo-2-(2-(3,4dichlorophenyl)hydrazinylidene)butanoic acid (2b), showing an IC50 value of 50 µM. For a preliminary assessment of their antivirulence properties the new derivatives were tested for their antibiofilm activity. The most active compound resulted 2a, which showed inhibition of about 60% against S. aureus ATCC 29213, S. aureus ATCC 25923, S. aureus ATCC 6538 and S. epidermidis RP62A at a screening concentration of 100 µM.

Isoxazolo[3,4-d]pyridazin-7(6H)-one derivatives endowed with antiproliferative Activity B. Maggio1, G. Cancemi1, D. Raffa1, M. V. Raimondi1, F. Plescia1, A. D’Anneo2,M. Lauricella3, G. Barone4, R. Bonsignore4, G. Daidone1 1. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Medicinal Chemistry and Pharmaceutical Technologies Section, University of Palermo, ViaArchirafi 32, 90123, Palermo, Italy 2. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo. 3.Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo. 4. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo. benedetta.maggio@unipa.it A screening carried out by NCI (Bethesda, USA) on compounds available in our laboratory,in order to ascertain their antiproliferative activity against a panel of 60 human tumor cell lines, allowed to discovery the 3,4-diphenylisoxazolo[3,4-d]pyridazin-7(6H)-one 1a [1] as an hit compound, often showing GI50values at sub-micromolar level. We synthesized some analogs of 1a, i.e.1b-gand other derivatives in which the NHgroup is variably alkylated, with the aim to obtain more active compounds as well as to perform structure-activity relationship(SAR) studies. We obtained a quite active antiproliferative compound, the 3,4-di-p-tolylisoxazolo[3,4-d]pyridazin-7(6H)- one 1d, and verified the importance for the antiproliferative activity of the aril, and not alkyl, groups linked to the isoxazolo-pyridazinone moiety. Studies performed on the cell cycle progression and on some cellular target (ATM, procaspase-2 proteins and H2AX histone) demonstrated that 1d produces an increase of the cell population in pre-G0/G1 and induces cellular death by apoptosis, damaging the DNA by double strand breaks. UV-vis titration and viscosity measurement showed that the compound is able to give an interaction with the B-DNA. 1. Renzi G., Dal Piaz V. (2004)Gazz. Chim. It.95: 1478–1491

New N-methyl and N-ethyl substitutions in the indazole nucleus are reported by reacting 3-(2-aminobenzamido)indazole and the appropriate trimethyl/triethyl orthobenzoate. Single crystal X-ray analysis confirms the N-ethylation position for the 3-(1-ethyl-1H-indazol-3-yl)-2-phenylquinazolin-4(3H)-one derivative 3f. Compounds 11a-d and 3a-d were tested to evaluate their antimicrobial, their antiproliferative activity and their COX inhibitory activities showing scarce or moderately antiproliferative activity and some inhibitory activity against COX-1 and COX-2.

Several new 2-(2-phenoxyacetamido)benzamides 17a-v, 21 and 22 were synthesized by stirring in pyridine the acid chlorides 16a-e and the appropriate5-R-4-R1-2-aminobenzamide 15a-e and initially evaluated in vitro for antiproliferative activity against the K562 (human chronic myelogenous leukemia) cell line. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). The most active compounds caused an arrest of K562 cells in the G0-G1 phase of cell cycle and induction of apoptosis, which was mediated by caspase activation.

Alcohol drinking during pregnancy and post-partum period is a major concern because of the persistent neurobehavioral deficits in the offspring, which include increased vulnerability to substance abuse (1). The intermittent pattern of alcohol consumption induces higher drinking levels and deeper neurobiological changes in addiction-related brain regions, with respect to traditional free-access paradigms in male rats (2, 3). Nevertheless, no studies investigated on the effects of the drinking pattern on female subjects during pregnancy and perinatal time. To this aim, this study explored the consequences of continuous vs. intermittent drinking pattern on maternal behaviour and on offspring vulnerability to alcohol, during adulthood. Dams were given two-bottle choice to water and 20% alcohol with either continuous- or intermittent access (CA vs IA), along a 12-week period. They suspended alcohol drinking during breeding and resumed alcohol self-administration from late gestation throughout lactation, when they were assessed for home-cage undisturbed maternal behaviour. In the adulthood, alcohol-exposed offspring were assessed for alcohol drinking behaviour in a free-choice paradigm and tested for the deprivation effect. Our results show that alcohol consumption and preference significantly decreased in IA group during pregnancy, returning to baseline during lactation. Alcohol drinking was able to disrupt spontaneous maternal behaviour, especially in IA exposed dams. On the other hand, perinatal CA exposure did not increase alcohol-drinking behaviour in the offspring with respect to controls, while rats perinatally exposed to IA displayed a high vulnerability to alcohol, in terms of drinking behaviour and deprivation effect. In conclusion, this study indicates for the first time that the pattern of alcohol consumption can be responsible for different extents of maternal behaviour disruption and detrimental consequences in the offspring. Therefore gender- but also pattern-related differences should be taken into account for contrasting alcohol abuse and dependence, especially during perinatal time. 1. McMurray MS, Williams SK, Jarrett TM, Cox ET, Fay EE, Overstreet DH, Walker CH, Johns JM. Neurotoxicol Teratol. 2008;30(6):475-86. 2. Stuber GD, Hopf FW, Hahn J, Cho SL, Guillory A, Bonci A. Alcohol Clin Exp Res. 2008 Oct;32(10):1714-20 3. George O, Sanders C, Freiling J, Grigoryan E, Vu S, Allen CD, Crawford E, Mandyam CD, Koob GF. Proc Natl Acad Sci U S A. 2012;109(44):18156-61

Alcohol consumption during perinatal periods is common, despite the warning of adverse effects on the foetal development. In female rats, the intermittent pattern of alcohol consumption is responsible for higher drinking levels and more profound disruption of maternal care than traditional continuous free-access paradigm, which can have persistent effects on the offspring. The environmental enrichment, a powerful form of experience-dependent plasticity that allows high cognitive, motor and sensory stimulations, is helpful for recovering from different neurological pathologies. Thus, this study aimed at exploring the effects of environmental enrichment on alcohol vulnerability and affective behaviour in the offspring that was perinatally exposed to continuous or intermittent alcohol. Dams were given two-bottle choice to water and 20% alcohol with either continuous- or intermittent access (CA vs IA), along a 12-week period. They were alcohol-deprived during breeding and resumed alcohol self-administration from late gestation and throughout lactation. Alcohol-exposed offspring, reared in either standard- or enriched- conditions, were assessed for alcohol drinking behaviour in a free-choice paradigm and were also tested for the deprivation effect. Moreover, they were tested for behavioural reactivity in the open field; anxiety-like behaviour in the elevated plus maze and depressive-like behaviour in the forced swim test during the drinking paradigm. Our results show that perinatal CA to alcohol did not increase alcohol-drinking behaviour with respect to controls. On the other hand, rats perinatally exposed to IA displayed a high vulnerability to alcohol, in terms of drinking behaviour and deprivation effect. The environmental enrichment was able to exert a protective role on alcohol vulnerability in perinatally IA exposed rats and controls, especially during relapse. Moreover, it was able to induce an increase in behavioural reactivity in the open field and a decrease in anxiety-like behaviour in the elevated plus maze, in both perinatally CA and IA exposed groups. In conclusion, the pattern of alcohol consumption during pregnancy and lactation can influence long-term alcohol vulnerability in the offspring. Rearing conditions that promote high cognitive, motor and sensory stimulations improve resilience to alcohol abuse and affective tone, although they cannot be sufficient to full recovery from detrimental effects of perinatal alcohol exposure.

Acetaldehyde (ACD), the first alcohol metabolite, plays a pivotal role in the rewarding, motivational and addictive properties of the parental compound. Many studies have investigated the role of ACD in mediating neurochemical and behavioral effects induced by alcohol administration, but very little is known about the modulation of neuropeptide systems following ACD intoxication and withdrawal. Indeed the neuropeptide Y (NPY) system is altered during alcohol withdrawal in key regions for cerebrocortical excitability and neuroplasticity. The primary goal of this research was to investigate the effects of ACD intoxication and withdrawal by recording rat behavior and by measuring neuropeptide Y immunoreactivity in hippocampus and NAcc, two brain regions mainly involved in processes which encompass neuroplasticity in alcohol dependence. Furthermore, on the basis of the involvement of endocannabinoidergic system in alcohol and ACD reinforcing effects, the role of the selective CB1 receptor antagonist AM281 in modulating NPY expression during withdrawal was assessed. Our results indicate that: i) ACD intoxication induced a reduction in NPY expression in hippocampus and NAcc; ii) symptoms of physical dependence, similar to alcohol's, were scored at 12h from the last administration of ACD; iii) NPY levels increased in early and prolonged acute withdrawal in both brain regions examined. The administration of AM281 was able to blunt signs of ACD-induced physical dependence; to modulate NPY levels, and to further increase NPY expression during ACD withdrawal both in hippocampus and NAcc. In conclusion, the present study shows that complex plastic changes take place in NPY system during ACD intoxication and subsequent withdrawal in rat hippocampal formation and NAcc. The pharmacological inhibition of CB1 signaling could counteract the neurochemical imbalance associated with ACD, and alcohol withdrawal, likely boosting the setting up of homeostatic functional recovery.

The aims of this study were to determine the distribution of risk factors associated with tinnitus analysing their role in the development of tinnitus and the effects of their interaction; to evidence the importance of a suitable and adequate clinical and audiologic assessment to avoid those modifiable risk factors responsible for cochlear dysfunction and tinnitus onset. 46 subjects with tinnitus and 74 controls were studied according to: age, sex, Body Mass Index (BMI), neck circumference, tobacco smoking, feeling fatigue or headache, self reporting snoring, hypertension, diabetes, coronary heart disease, and/or hyperlipidemia, and laboratory finding as lipid profile and levels of reactive oxygen metabolites (d-ROM). Audiological assessment was performed by multi-frequency audiometry (PTA0.5–16 kHz) and transient-evoked otoacoustic emissions (TEOAE diagnostic). Univariate analysis was performed to examine the association between determinants and occurrence of tinnitus; Mantel–Haenszel test (G.or) was used to investigate the joint effect of determinants on tinnitus. Tinnitus was more frequent among males with age >50 years; BMI >30 kg/m2, neck circumference >40 cm, headache, hypertension, hypercholesterolemia resulted significant risk factors for tinnitus (P < 0.0001). Tinnitus group had more comorbidity (P < 0.0001) and worse audiometric thresholds (60.87 Vs 21.62 % hearing loss; P < 0.0001) with respect to control group. The interaction between hypertension–BMI ≥ 30 kg/m2 (G.or = 8.45) and smoking–hypercholesterolemia (G.or = 5.08) increases the risk of tinnitus (P < 0.0001). Our results underline that several factors either individually or jointly contribute to tinnitus onset; a comprehensive knowledge about tinnitus risk factors and associated clinical conditions could contribute to minimizing this disorder.

Women show higher vulnerability for neuroadaptation to alcohol, which may contribute to negative emotional state during withdrawal (Sharrett-Field et al., 2013; Koob and Le Moal, 1997). This study aimed at exploring the effects of different patterns of voluntary ethanol consumption on female rat"s affective behaviour during withdrawal. Female rats underwent 12-week-, 2-bottle choice- continuous or intermittent (3 days/week ) access to 20% ethanol and were respectively named CARs and IARs. They were tested for alcohol preference; dysphoric-like state during withdrawal (24-48h); depressive- and anhedonic-like behaviours explored by forced swim- and saccharin preference tests; anxiety-like behaviour by the EPM and behavioural reactivity in the OF arena. During the 12-week self-administration procedure, IARs displayed higher ethanol consumption and preference, both after 1h and 24h, with respect to CARs (p

Neuropeptide Y (NPY) acts as an endogenous anxiolytic, and, like endocannabinoids, plays an important role in the regulation of neuronal excitability during ethanol withdrawal (Rubio et al., 2011). Since acetaldehyde is considered a mediator of ethanol central effects, this research aims at investigating, following intoxication and during withdrawal, the effects of acetaldehyde on NPY expression in brain areas particularly vulnerable to alcohol, and the influence of cannabinoid system on it. Rats underwent acetaldehyde intoxication (450mg/kg, i.g., 4 times daily for 4 days); AM281, a CB1 selective antagonist (2,5 mg/kg, i.p.) was administered during abstinence. Immunohistochemical analysis on NPY expression was performed at 1h, 16h, 72h after the last acetaldehyde administration, in NAcc and hippocampus. NPY expression in NAcc and hippocampus (p

Neurosteroids can alter neuronal excitability interacting with specific neurotransmitter receptors, thus affecting several functions such as cognition and emotionality. In this study, we investigated, in adult male rats, the effects of the acute administration of pregnenolone-sulfate (PREGS) (10 mg/Kg, s. c.) on cognitive processes using the Can test, a non aversive spatial/visual task which allows the assessment of spatial information-acquisition during the baseline training, and of memory retention in the longitudinal study. Furthermore, on the basis of PREGS pharmacological profile, the modulation of depressive-like behaviour was also evaluated in the forced swim test (FST). Our results indicate that acute PREGS induces: an improvement in spatial orientation-acquisition and in reference memory, during the baseline training; a strengthening effect on reference and working memory during the longitudinal study. A decrease in immobility time in the FST has also been recorded. In conclusion, PREGS exerts enhancing properties on acquisition, consolidation and retrieval of spatial information, probably due of improved hippocampal-dependent memory processes. The additional antidepressant effect observed in the FST can provide further evidence in support of the potential of PREGS as a therapeutic tool for the treatment of cognitive deficits associated with mood disorders. This article is part of a Special Issue entitled: insert SI title.