Ursodeoxycholic acid: a potential anti-arrhythmic and anti-fibrotic agent in adult hearts

Acute myocardial ischaemia and reperfusion (I-R) are major causes of ventricular arrhythmias. In the chronic post-ischaemic heart, the presence of a healed fibrotic scar contributes to the occurrence of malignant arrhythmias, and development of post-myocardial infarction (MI) left ventricular (LV) remodelling and heart failure (HF). The aim of the work in this thesis was to investigate if ursodeoxycholic acid (UDCA) protects against acute I-R-induced arrhythmias, and if it plays cardioprotective and anti-arrhythmic roles in the chronic post-MI adult myocardium. An ex vivo rat model of acute I-R was used to study the effect of UDCA on arrhythmia incidence. UDCA administration reduced acute ischaemia-induced arrhythmias, with no effect on reperfusion arrhythmias. The antiarrhythmic effect of UDCA is partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity (CV) slowing, and the preservation of Connexin43 phosphorylation during acute ischaemia. Multiple in vitro models of cardiac fibrosis were used to study the potential of UDCA as treatment of cardiac fibrosis. UDCA was proven to reduce cardiac fibrosis and preserve the associated changes in contractile functions and electrophysiology. The antifibrotic mechanism of action of UDCA is partially mediated by TGR5 modulation via dephosphorylation of ERK protein. A sixteen-week post-MI model was generated to explore the effects of UDCA on late post-MI arrhythmias and LV remodeling. UDCA prevented the adverse LV remodeling associated with the progression of MI and reduced fibrosis and the healed ischaemic border zone (IBZ) sizes. This resulted in reduced late susceptibility to ventricular arrhythmias and improved CV across the IBZ in UDCA-treated hearts at 16 weeks post MI. We generated robust novel data highlighting the potential application of UDCA in the prevention of ventricular arrhythmias during acute MI in the adult myocardium as well as against cardiac arrhythmias that are associated with cardiac fibrosis, due to its cardioprotective effect in the post-MI heart.Open Acces

Experimental Set-Up of the Production Process and Mechanical Characterization of Metal Foams Manufactured by Lost-PLA Technique with Different Cell Morphology

A flexible and versatile method for manufacturing open-cell metal foams, called lost- PLA, is presented in this work. With a double extruder 3D printer (FDM, Ultimaker S3, Utrecht, The Netherlands), it is possible to make polymer-based samples of the lost model. Through CAD modeling, different geometries were replicated so as to get black PLA samples. This method combines the advantages of rapid prototyping with the possibility of manufacturing Al-alloy specimens with low time to market. The production process is articulated in many steps: PLA foams are inserted into an ultra-resistant plaster mix, after which the polymer is thermally degraded. The next step consists of the gravity casting of the EN-6082 alloy in the plaster form, obtaining metal foams that are interesting from a technological point of view as well as with respect to their mechanical properties. These foam prototypes can find application in the automotive, civil and aeronautical fields due to their high surface/weight ratio, making them optimal for heat exchange and for the ability to absorb energy during compression. The main aspects on which we focus are the set-up of the process parameters and the characterization of the mechanical properties of the manufactured samples. The main production steps are examined at first. After that, the results obtained for mechanical performance during static compression tests with different geometry porosities are compared and discussed. The foam with truncated octahedron cells was found to show the highest absorbed energy/relative density ratio

Quantitation of cellular deoxynucleoside triphosphates

Eukaryotic cells contain a delicate balance of minute amounts of the four deoxyribonucleoside triphosphates (dNTPs), sufficient only for a few minutes of DNA replication. Both a deficiency and a surplus of a single dNTP may result in increased mutation rates, faulty DNA repair or mitochondrial DNA depletion. dNTPs are usually quantified by an enzymatic assay in which incorporation of radioactive dATP (or radioactive dTTP in the assay for dATP) into specific synthetic oligonucleotides by a DNA polymerase is proportional to the concentration of the unknown dNTP. We find that the commonly used Klenow DNA polymerase may substitute the corresponding ribonucleotide for the unknown dNTP leading in some instances to a large overestimation of dNTPs. We now describe assay conditions for each dNTP that avoid ribonucleotide incorporation. For the dTTP and dATP assays it suffices to minimize the concentrations of the Klenow enzyme and of labeled dATP (or dTTP); for dCTP and dGTP we had to replace the Klenow enzyme with either the Taq DNA polymerase or Thermo Sequenase. We suggest that in some earlier reports ribonucleotide incorporation may have caused too high values for dGTP and dCTP

Virtual Reality for Neuroarchitecture: Cue Reactivity in Built Spaces

Domestic and urban environments are associated to our life experiences and behaviors. These environments may acquire an emotional and motivational value and, in turn, shape our behaviors. Although there is a well-established knowledge of the effects of built space features on perception, feelings, and affective responses (Ulrich, 1991), only a limited attention has been however paid to physical space-induced motivated behaviors. There is still a strong attitude to consider the control of motivated behaviors as a matter of individual desires, free will, moral choices, executive control, etc.—and not as the interaction between environment and personality, genetics, and brain mechanisms. Recently, there has been a convergent agreement from architects, designers, psychologists, and neuroscientists about the multifactorial nature of the reciprocal interaction between humans and built space, and how it could impact on well-being psychological distress and risky behaviors (Sternberg, 2009). The emerging interdisciplinary field of “neuroarchitecture” developed conceptual paradigms and empirical frameworks based on the interaction between brain and built spaces (see Academy of Neuroscience for Architecture; www.anfarch.org). Within this framework, we would like to propose the “Cue Reactivity” phenomenon as a paradigmatic example of such as interaction. Cue reactivity (C-R) is the adaptive response to salient information in the environment (Niaura et al., 1988). Salient information is that associated to drugs, sex, palatable food, and to a variety of natural and non-natural rewards (such as gambling, shopping, etc.). Drug C-R manifests itself as an array of responses to stimuli previously associated to drug effect. The detrimental consequence of C-R is relapse to drug-seeking and drug-taking (Rohsenow et al., 1991). On the other hand, C-R is an evolutionary phenotype of the interaction with the environment: in fact, spatial context rich of reward-related cues may stimulate both positive and risky motivated behaviors. In this Opinion paper, we will show that identification and design of specific physical space features may affect mental health, and that indoor and furniture of drinking venues are associated to alcohol use. Based on what we know about C-R, and on the effects of built spaces on psychological and behavioral processes, we think that more research is now possible to plan and design research-based “C-R-free situations.” For instance, investigations on outdoor and indoor features associated to C-R may help to develop “motivational safer built environments.” The complexity of real world investigations is not however easily modeled in the laboratory, but technologies like virtual reality may offer the possibility to increase subject's presence in a spatial context simulation and, in the meantime, the control of the experimental parameters (García-Rodríguez et al., 2012). For these reasons, we propose virtual reality as a methodological approach in-between naturalistic and experimental lab setting for a better understanding of built space features affecting C-R.The “5per mille 2012” research grant by the Italian Cancer League (Lega Italiana Lotta per i Tumori, LILT) supported the study (PI: CC) and research grant for GB. LILT also supported CC and SF with educational grants

Cerebrospinal fluid anti-Epstein-Barr virus specific oligoclonal IgM and IgG bands in patients with clinically isolated and Guillain-Barré syndrome

Epstein-Barr virus (EBV) has been implicated in multiple sclerosis (MS) pathogenesis. We aimed to assess the frequency of EBV-specific IgG and IgM oligoclonal bands (OCB) in cerebrospinal fluid (CSF) of 50 patients with clinically isolated syndrome (CIS) and in 27 controls with Guillain-Barré syndrome (GBS). Furthermore, we assessed correlations between the presence of OCB and CIS patients' CSF, MRI, and clinical variables. There was no difference in the proportion of CIS and GB patients with positivity for anti-EBV-specific IgG/IgM OCB. There were no correlations between OCB and analyzed variables, nor were they predictive of a higher disability at 3 years

Linking neuroanatomical abnormalities in autism spectrum disorder with gene expression of candidate ASD genes: A meta-analytic and network-oriented approach

BACKGROUND: Autism spectrum disorder (ASD) is a set of developmental conditions with widespread neuroanatomical abnormalities and a strong genetic basis. Although neuroimaging studies have indicated anatomical changes in grey matter (GM) morphometry, their associations with gene expression remain elusive. METHODS: Here, we aim to understand how gene expression correlates with neuroanatomical atypicalities in ASD. To do so, we performed a coordinate-based meta-analysis to determine the common GM variation pattern in the autistic brain. From the Allen Human Brain Atlas, we selected eight genes from the SHANK, NRXN, NLGN family and MECP2, which have been implicated with ASD, particularly in regards to altered synaptic transmission and plasticity. The gene expression maps for each gene were built. We then assessed the correlation between the gene expression maps and the GM alteration maps. Lastly, we projected the obtained clusters of GM alteration-gene correlations on top of the canonical resting state networks, in order to provide a functional characterization of the structural evidence. RESULTS: We found that gene expression of most genes correlated with GM alteration (both increase and decrease) in regions located in the default mode network. Decreased GM was also correlated with gene expression of some ASD genes in areas associated with the dorsal attention and cerebellar network. Lastly, single genes were found to be significantly correlated with increased GM in areas located in the somatomotor, limbic and ganglia/thalamus networks. CONCLUSIONS: This approach allowed us to combine the well beaten path of genetic and brain imaging in a novel way, to specifically investigate the relation between gene expression and brain with structural damage, and individuate genes of potential interest for further investigation in the functional domain

A virtual reality study on postretrieval extinction of smoking memory reconsolidation in smokers

Exposure to smoking-related stimuli may induce the reconsolidation of smoking-related memories in smokers. Research has proposed that extinction applied after the retrieval of a smoking memory may inhibit reconsolidation and prevent craving. The aim of this study was to test the effect of postretrieval extinction (PRE) on the reconsolidation of smoking memory by using a virtual reality (VR) simulation in smokers. On the day 1 session, the study exposed 46 smokers to a neutral and then to a smoking VR scenario under a fixed-block protocol. On day 2, the study randomized participants into three groups (G) and exposed them to a 15-s VR immersion in smoking (G1, G3) or neutral (G2) scenario for memory retrieval. After 15 min, the study exposed G1 and G2 to a VR PRE during the temporal window of memory vulnerability, whereas the study exposed G3 to extinction immediately after retrieval. On day 3, the study exposed all groups to neutral and smoking scenarios similar to day 1. All groups significantly increased craving for cigarettes after exposure to the smoking scenario on day 1 (p 0.01). On day 3, VR PRE after a 15-second VR smoking memory retrieval was able to inhibit reconsolidation in G1, but not in G3 exposed to PRE before the window of vulnerability, or in G2 not exposed to the smoking memory retrieval. These findings show the superiority of VR PRE after smoking memory retrieval compared to a standard extinction procedure

Climate Change and Childhood Respiratory Health: A Call to Action for Paediatricians

Climate change (CC) is one of the main contributors to health emergencies worldwide. CC appears to be closely interrelated with air pollution, as some pollutants like carbon dioxide (CO2), nitrogen oxides (NOx) and black carbon are naturally occurring greenhouse gases. Air pollution may enhance the allergenicity of some plants and, also, has an adverse effect on respiratory health. Children are a uniquely vulnerable group that suffers disproportionately from CC burden. The increasing global warming related to CC has a big impact on plants' lifecycles, with earlier and longer pollen seasons, as well as higher pollen production, putting children affected by asthma and allergic rhinitis at risk for exacerbations. Extreme weather events may play a role too, not only in the exacerbations of allergic respiratory diseases but, also, in favouring respiratory infections. Even though paediatricians are already seeing the impacts of CC on their patients, their knowledge about CC-related health outcomes with specific regards to children's respiratory health is incomplete. This advocates for paediatricians' increased awareness and a better understanding of the CC impact on children's respiratory health. Having a special responsibility for children, paediatricians should actively be involved in policies aimed to protect the next generation from CC-related adverse health effects. Hence, there is an urgent need for them to take action and successfully educate families about CC issues. This paper aims at reviewing the evidence of CC-related environmental factors such as temperature, humidity, rainfall and extreme events on respiratory allergic diseases and respiratory infections in children and proposing specific actionable items for paediatricians to deal with CC-related health issues in their clinical practice

Abnormal Circadian Modification of A\u3b4-Fiber Pathway Excitability in Idiopathic Restless Legs Syndrome

Restless legs syndrome (RLS) is characterized by unpleasant sensations generally localized to legs, associated with an urge to move. A likely pathogenetic mechanism is a central dopaminergic dysfunction. The exact role of pain system is unclear. The purpose of the study was to investigate the nociceptive pathways in idiopathic RLS patients. We enrolled 11 patients (mean age 53.2\u2009\ub1\u200919.7 years; 7 men) suffering from severe, primary RLS. We recorded scalp laser-evoked potentials (LEPs) to stimulation of different sites (hands and feet) and during two different time conditions (daytime and nighttime). Finally, we compared the results with a matched control group of healthy subjects. The A\u3b4 responses obtained from patients did not differ from those recorded from control subjects. However, the N1 and the N2-P2 amplitudes' night/day ratios after foot stimulation were increased in patients, as compared to controls (N1: patients: 133.91\u2009\ub1\u200950.42%; controls: 83.74\u2009\ub1\u200934.45%; p = 0.016; A\u3b4-N2-P2: patients: 119.15\u2009\ub1\u200915.56%; controls: 88.42\u2009\ub1\u200923.41%; p = 0.003). These results suggest that RLS patients present circadian modifications in the pain system, which are not present in healthy controls. Both sensory-discriminative and affective-emotional components of pain experience show parallel changes. This study confirms the structural integrity of A\u3b4 nociceptive system in idiopathic RLS, but it also suggests that RLS patients present circadian modifications in the pain system. These findings could potentially help clinicians and contribute to identify new therapeutic approaches