Design and synthesis of 2-oxo-1,2-dihydropyridine-3-carboxamide derivatives as new modulators of endocannabinoid system.

Cannabinoid receptors and endocannabinoid ligands, together with the enzymes implicated in endocannabinoid biosynthesis, degradation and transport constitute the endocannabinoid system (ECS). It is involved in several physiological and pathological processes. Previously in a research program focused on the discovery of new CBR ligands, a series of 2-oxo-1,2- dihydropyridine-3-carboxamide derivatives was developed. These compounds showed potent and selective affinity toward CB2R. Moreover, it was discovered that the substituent in position C5 of the pyridine ring was the main responsible for the functional activity of this class of compounds. After the insertion of a methyl group at the C6 position of the pyridine ring was investigated. It was found that the presence of a small substituent in that position did not affect both the CBR affinity and the functional activity within this class of compounds. In this thesis, novel potential CBR ligands were synthesized modifying the 2-oxo-1,2-dihydropyridine-3-carboxamide nucleus with different approaches: 1) shift of the methyl group of 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives from C6 to C4 position of the pyridine ring; 2) shift of the substituents of 2-oxo-1,2-dihydropyridine-3-carboxamide derivatives from C5 to C4 position of the pyridine ring; 3) insertion of a further substituent in position 4 of the pyridine ring in the 2-oxo-1,2-dihydropyridine-3-carboxamide derivatives

Effects of opioids on proximal renal tubular cells undergoing ATP depletion.

Abstract This study investigated the effect of morphine, fentanyl, butorphanol and buprenorphine on viability and caspase-3 activity in renal proximal tubular cells exposed to opioids for 2 h before or 12 h after chemical anoxia. Cell viability decreased regardless the treatment although intracellular ATP content was elevated in morphine and fentanyl pre-treated cells at 12 h. Anoxia increased caspase activity but this effect was significantly reduced in cells treated before or after with morphine, fentanyl and in cell treated with butorphanol for 12 h. No influence of buprenorphine was detected. Morphine, fentanyl and butorphanol might have protective effects during kidney ischemia

The role of Attachment Insecurity in the emergency of anxiety symptoms in children and adolescent with migraine: an empirical study

Background: It is widely recognised that there are associations between headache, psychiatric comorbidity and attachment insecurity in both adults and children. The aims of this study were: 1) to compare perceived attachment security and anxiety in children and adolescents with migraine without aura and a healthy control group; 2) to test whether the child’s perceived security of attachment to the mother and the father mediated the association between migraine and anxiety. Methods: One hundred children and adolescents with Migraine without Aura were compared with a control group of 100 children without headache. The Security Scale (measures perceived security of attachments) and the Self-Administered Psychiatric Scales for Children and Adolescents, a measure of anxiety symptoms, were administered to all participants. Results: The clinical group had lower attachment security than the control group and higher scores on all anxiety scales. Anxiety was negatively correlated with attachment. Children’s attachment to their mother mediated the increase in global anxiety in the clinical group. Insecure paternal attachment was associated with greater insecurity in maternal attachment, suggesting that there is a complex pathway from migraine to anxiety symptoms mediated by perceived insecurity of paternal attachment and hence also by perceived insecurity of maternal attachment. Conclusion: These results suggest that insecure parental attachment may exacerbate anxiety in children and adolescents with migraine and point to the importance of multimodal interventions, perhaps taking account of family relationships, for children and adolescents with migraine

Integration of capillary and EWOD technologies for autonomous and low-power consumption micro-analytical systems

This work presents a miniaturized system combining, on the same microfluidic chip, capillarity and electrowetting-on-dielectric (EWOD) techniques for movement and control of fluids. The change in hydrophobicity occurring at the edge between a capillary channel and a hydrophobic layer is successfully exploited as a stop-and-go valve, whose operation is electronically controlled through the EWOD electrodes. Taking into account the variety of microfluidic operation resulting from the combination of the two handling techniques and their characteristic features, this work prompts the development of autonomous, compact and low-power consumption lab-on-chip systems

Correlating the Clinical and Genetic Features of Benign Familial Neonatal Seizures (BFNS) with the Functional Consequences of Underlying Mutations

Almost ten years have passed since the identification of Kv7.2 and Kv7.3, the genes altered in benign familial neonatal seizures (BFNS), a familial autosomal dominant focal epilepsy of the newborn. Despite the rarity of the disease, clinical and genetic data have been gathered from more than 50 BFNS-affected families; these studies reveal that each family harbours a specific disease-causing mutation, and that the mutation-induced functional changes range from a subtle alteration in channel behaviour to a complete ablation of channel function. Prompted by the recent identification of peculiar gating changes in Kv7.2 subunits caused by novel mutations responsible for BFNS, in the present work we attempt to link, whenever possible, the specific genetic defect with the clinical evolution of the disease in the affected families on one side, and, on the other, with the functional defects revealed by expression studies. Such genotype-phenotype correlations may provide clues on the pathogenesis of the wide variety of neuropsychiatric manifestations often associated to BFNS, and should foster our attempts to gain more detailed functional information which might help to elucidate the pathogenetic mechanisms of the disease

Small-angle neutron scattering and Molecular Dynamics structural study of gelling DNA nanostars

DNA oligomers with properly designed sequences self-assemble into well defined constructs. Here, we exploit this methodology to produce bulk quantities of tetravalent DNA nanostars (each one composed by 196 nucleotides) and to explore the structural signatures of their aggregation process. We report small-angle neutron scattering experiments focused on the evaluation of both the form factor and the temperature evolution of the scattered intensity at a nano star concentration where the system forms a tetravalent equilibrium gel. We also perform molecular dynamics simulations of one isolated tetramer to evaluate the form factor theoretically, without resorting to any approximate shape. The numerical form factor is found to be in very good agreement with the experimental one. Simulations predict an essentially temperature independent form factor, offering the possibility to extract the effective structure factor and its evolution during the equilibrium gelation.Comment: 9 pages, 5 figure

Assessing Mental Pain as a Predictive Factor of Suicide Risk in a Clinical Sample of Patients with Psychiatric Disorders

According to contemporary suicidology, mental pain represents one of the main suicide risk factors, along with more traditional constructs such as depression, anxiety and hopelessness. This work aims to investigate the relationship between the levels of mental pain and the risk to carry out suicide or suicide attempt in the short term in order to understand if a measurement of mental pain can be used as a screening tool for prevention. For this purpose, 105 outpatients with psychiatric diagnosis were recruited at the university hospital of Varese during a check-up visit and were assessed by using psychometric scales of mental pain levels, hopelessness, anxiety and depression. Clinical and sociodemographic variables of the sample were also collected. A period of 18 months following the recruitment was observed to evaluate any suicides or attempted suicides. Subjects numbering 11 out of 105 committed an attempted suicide. From statistical analyses, high values of the Beck Depression Inventory (BDI-II), Mental Pain Questionnaire (OMMP) and Hamilton Rating Scale for Depression (HAM-D) scales showed a significant association with the risk of carrying out a suicide attempt and, among these, OMMP and BDI-II showed characteristics of good applicability and predictivity proving suitable to be used as potential tools for screening and primary prevention of suicidal behavior