FAAH inhibition as a preventive treatment for migraine: A pre-clinical study

Abstract Background Fatty-acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of endogenous fatty-acid amides, including the endocannabinoid anandamide (AEA). We previously reported that the peripherally restricted FAAH inhibitor URB937, which selectively increases AEA levels outside the central nervous system, reduces hyperalgesia and c-Fos expression in the trigeminal nucleus caudalis (TNC) and the locus coeruleus in an animal model of migraine based on nitroglycerin (NTG) administration. Aim To further investigate the relevance of FAAH inhibition in the NTG animal model of migraine by testing the effects of the globally active FAAH inhibitor URB597. Methods Our experimental approach involved mapping neuronal c-Fos protein expression, measurement of AEA levels in brain areas and in trigeminal ganglia, evaluation of pain-related behavior and quantification of molecular mediators in rats that received URB597 (2 mg/kg i.p.) either before or after NTG administration (10 mg/kg, i.p.). Results Pre-treatment with URB597 significantly reduced c-Fos immunoreactivity in the TNC and inhibited NTG-induced hyperalgesia in the orofacial formalin test. This behavioral response was associated with a decrease in neuronal nitric oxide synthase, calcitonin gene-related peptide and cytokine gene expression levels in central and peripheral structures. Administration of URB597 after NTG had no such effect. Conclusions The findings suggest that global FAAH inhibition may offer a therapeutic approach to the prevention, but not the abortive treatment, of migraine attacks. Further studies are needed to elucidate the exact cellular and molecular mechanisms underlying the protective effects of FAAH inhibition

Civility and Trust in Social Media

Abstract Social media have been credited with the potential of reinvigorating trust by offering new opportunities for social and political participation. This view has been recently challenged by the rising phenomenon of online incivility, which has made the environment of social networking sites hostile to many users. We conduct a novel experiment in a Facebook setting to study how the effect of social media on trust varies depending on the civility or incivility of online interaction. We find that participants exposed to civil Facebook interaction are significantly more trusting. In contrast, when the use of Facebook is accompanied by the experience of online incivility, no significant changes occur in users' behavior. These results are robust to alternative configurations of the treatments

Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine.

Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia - an animal model of migraine - and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-inflammatory cytokines along with tissue levels of anandamide and palmitoylethanolamide (PEA), an endogenous agonist of peroxisome proliferator-activated receptor type-a (PPAR-a), which is also a FAAH substrate. In the acute migraine model, we also investigated the effect of subtype-selective antagonist for cannabinoid receptors 1 and 2 (AM251 and AM630, respectively) on nocifensive behavior and on levels of neuropeptides and pro-inflammatory cytokines. In the acute migraine paradigm, URB937 significantly reduced hyperalgesia in the orofacial formalin test when administered either before or after NTG. This effect was accompanied by an increase in anandamide and PEA levels in target neural tissue, depended upon CB1 receptor activation, and was associated with a decrease in calcitonin gene-related peptide (CGRP), substance P and cytokines TNF-alpha and IL-6 mRNA. Similar effects were observed in the chronic migraine paradigm, where URB937 counteracted NTG-induced trigeminal hyperalgesia and prevented the increase in neuropeptide and cytokine transcription. The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways

The mood stabilizing properties of AF3581, a novel potent GSK-3β inhibitor

Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzymeand highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients

Dilated-Hypokinetic Evolution of Hypertrophic Cardiomyopathy Prevalence, Incidence, Risk Factors, and Prognostic Implications in Pediatric and Adult Patients

ObjectivesThis study sought to investigate the incidence, risk factors, and prognosis of dilated-hypokinetic evolution in a large cohort of patients with hypertrophic cardiomyopathy (HCM) followed up at a cardiology center serving both the pediatric and the adult population.BackgroundThe available data on this evolution of HCM mainly regards prevalence (rather than incidence) in adults, with very little being known about the pediatric population.MethodsA total of 222 consecutive HCM patients (65% men, 19% ≤18 years old) were prospectively evaluated for a mean follow-up of 11 ± 9 years.ResultsA diagnosis of dilated-hypokinetic HCM was made in 12 patients at first evaluation (11 without previous septal myectomy surgery; prevalence, 4.9%). Twelve of the 210 patients with classic HCM at first evaluation underwent dilated-hypokinetic evolution (incidence, 5.3/1,000 patient-years). Patients with prevalent/incident dilated-hypokinetic evolution were younger at first evaluation (32 ± 14 years vs. 41 ± 21 years, p = 0.04) and more often had a family history of HCM (61% vs. 26%, p = 0.002) or sudden death (43% vs. 19%, p = 0.01) with respect to patients who maintained classic HCM. Moreover, they showed greater interventricular septum (23 ± 3 mm vs. 19 ± 6 mm, p = 0.004) and posterior wall (15 ± 3 mm vs. 13 ± 4 mm, p = 0.006) thickness. Cardiovascular death-free survival was lower among patients with dilated-hypokinetic HCM (p < 0.04). Cox proportional hazards regression analysis identified left ventricular wall thickness (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 1.01 to 1.14; p = 0.03) and end-diastolic diameter (HR = 1.08; 95% CI 1.04 to 1.11; p = 0.0001) as independent predictors of cardiovascular death.ConclusionsDilated-hypokinetic evolution is rare but not exceptional in HCM. Young age at diagnosis, family history of HCM, and greater wall thickness are incremental risk factors for dilated-hypokinetic HCM, which carries an ominous prognosis

Civility and trust in social media

Social media have been credited with the potential of reinvigorating trust by offering new opportunities for social and political participation. This view has been recently challenged by the rising phenomenon of online incivility, which has made the environment of social networking sites hostile to many users. We conduct a novel experiment in a Facebook setting to study how the effect of social media on trust varies depending on the civility or incivility of online interaction. We find that participants exposed to civil Facebook interaction are significantly more trusting. In contrast, when the use of Facebook is accompanied by the experience of online incivility, no significant changes occur in users’ behavior. These results are robust to alternative configurations of the treatments

Diagnosis, treatment and prevention of pediatric obesity: consensus position statement of the Italian Society for Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics

The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention.The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase

Le mappe concettuali come mediatori di cambiamento

Il contributo propone una riflessione sulle mappe concettuali nella didattica come strumento per stimolare la rappresentazione visiva di un processo cognitivo elaborato da parte degli studenti. In particolare saranno presentati i risultati di una ricerca condotta dal gruppo di ricerca "Laboratorio Inclusione e Tecnologie (LAB-INT) del Dipartimento di Scienze dell'Educazione (Università di Bologna