Image1_Seizure susceptibility to various convulsant stimuli in the BTBR mouse model of autism spectrum disorders.TIFF

Background: Autism spectrum disorders (ASDs) are one of the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact on society. Interestingly, several systematic reviews and meta-analyses documented a bidirectional link between epilepsy and ASD, supporting the hypothesis that both disorders may have common neurobiological pathways. According to this hypothesis, an imbalance of the excitatory/inhibitory (E/I) ratio in several brain regions may represent a causal mechanism underpinning the co-occurrence of these neurological diseases.Methods: To investigate this bidirectional link, we first tested the seizure susceptibility to chemoconvulsants acting on GABAergic and glutamatergic systems in the BTBR mice, in which an imbalance between E/I has been previously demonstrated. Subsequently, we performed the PTZ kindling protocol to study the impact of seizures on autistic-like behavior and other neurological deficits in BTBR mice.Results: We found that BTBR mice have an increased susceptibility to seizures induced by chemoconvulsants impairing GABAA neurotransmission in comparison to C57BL/6J control mice, whereas no significant difference in seizure susceptibility was observed after administration of AMPA, NMDA, and Kainate. This data suggests that deficits in GABAergic neurotransmission can increase seizure susceptibility in this strain of mice. Interestingly, BTBR mice showed a longer latency in the development of kindling compared to control mice. Furthermore, PTZ-kindling did not influence autistic-like behavior in BTBR mice, whereas it was able to significantly increase anxiety and worsen cognitive performance in this strain of mice. Interestingly, C57BL/6J displayed reduced sociability after PTZ injections, supporting the hypothesis that a tight connection exists between ASD and epilepsy.Conclusion: BTBR mice can be considered a good model to study epilepsy and ASD contemporarily. However, future studies should shed light on the mechanisms underpinning the co-occurrence of these neurological disorders in the BTBR model.</p

Monitoring safety and use of old and new treatment options for type 2 diabetic patients: a two-year (2013–2016) analysis

<p><b>Objective</b>: To compare patients’ and physicians’ perceptions regarding effectiveness and tolerability of non-insulin hypoglycemic drugs in a cohort of type 2 diabetic patients; to verify whether a possible tridimensional link between effectiveness, tolerability, and adherence affects long-term therapeutic outcomes.</p> <p><b>Methods</b>: A two-year observational study was performed in 1389 Type 2 diabetic patients by involving general practitioner clinics and Diabetes Centers. A decimal scale and the Morisky questionnaire were used, respectively, to assess effectiveness and tolerability perceptions, and medication adherence.</p> <p><b>Results</b>: Physicians perceived therapy as more efficacious compared to their patients: perceived effectiveness was steady for physicians during the study whereas patients’ perception not significantly decreased (mean score from >8 to 7.84 ± 1.69). Physicians assigned higher tolerability scores compared to patients but only at the beginning of the study; interestingly, physicians’ tolerability perception was poorer than patients’ perception at last follow-up (mean score = 7.57 ± 1.40 vs. 7.88 ± 1.84). Favorable (score >7) patients’ perceptions about treatment effectiveness and tolerability were associated with higher adherence. Patients showed medium adherence across the study.</p> <p><b>Conclusions</b>: A mutual relationship between clinical effectiveness, adverse drug reactions, and adherence has been established, significantly impacting the clinical management of diabetic patients. A careful monitoring of this link by clinicians appears therefore necessary.</p

Synthesis and Biological Characterization of 3‑Substituted 1<i>H</i>‑Indoles as Ligands of GluN2B-Containing <i>N</i>‑Methyl‑d‑aspartate Receptors. Part 2

In the course of the identification of new indole derivatives targeting GluN2B-subunit-containing <i>N</i>-methyl-d-aspartate (NMDA) receptor, the (<i>N</i>-1<i>H</i>-indol-6-methanesulfonamide-3-yl)-2-(4-benzylpiperidin-1-yl)­ethanone (<b>10b</b>) was identified as a potent ligand for this NMDA receptor subunit. It displays very high binding affinity (IC₅₀ of 8.9 nmol) for displacement of [³H]­ifenprodil, thus showing improved potency with respect to the previously reported analogues as confirmed by functional assay. This finding was consistent with the docking pose of compound <b>10b</b> within the binding pocket localized in the GluN1-GluN2B subunit interface of NMDA receptor tetraheteromeric complex

Adverse drug reactions reporting in Calabria (Southern Italy) in the four-year period 2011-2014: impact of a regional pharmacovigilance project in light of the new European Legislation

<p><b>Background</b>: The number of suspected adverse drug reactions (ADRs) yearly submitted to the Italian Network of Pharmacovigilance (RNF) has progressively increased after the new European Pharmacovigilance legislation (July 2012). These results have mostly reflected the agreements between Italian Medicines Agency (AIFA) and Italian Regions, enabling the implementation of active pharmacovigilance projects. A project was funded by the AIFA in Calabria region (Southern Italy) in 2010 to increase ADRs reporting and promote a safer medicines’ use. Based on this background, we investigated the trend of ADRs in Calabria in 2011–2014, trying to analyze the possible entailments of the new law.</p> <p><b>Methods</b>: Quantitative and descriptive analysis of ADRs submitted by Calabrian healthcare professionals and patients to the RNF database between 2011 and 2014.</p> <p><b>Results</b>: A sharp rise in regional reporting rate was observed over study period. Calabrian Pharmacovigilance system completely fulfilled the World Health Organization gold standard for ADR reporting rate, both in 2013 and 2014. However, heterogeneity was observed regarding reporting health facilities, healthcare professionals and patients among the study years.</p> <p><b>Conclusions</b>: These findings reflect the success of the project performed in Calabria. However, this initiative should go on in the next future to obtain better and more homogeneous reporting behavior.</p

General characteristics of the study population.

<p>General characteristics of the study population.</p

Logistic regression analysis with enthesis hypoechogenicity, thickening, enthesophyte, cortical irregularity as dependent variables after correction for body mass index.

<p>Logistic regression analysis with enthesis hypoechogenicity, thickening, enthesophyte, cortical irregularity as dependent variables after correction for body mass index.</p

General characteristics of the study population.

<p>General characteristics of the study population.</p

Metabolic characteristics of the study population.

<p>Metabolic characteristics of the study population.</p

Univariate and BMI-adjusted correlation analyses with plantar fascia enthesis thickness as dependent variable.

<p>Univariate and BMI-adjusted correlation analyses with plantar fascia enthesis thickness as dependent variable.</p

Nonpsychotropic Plant Cannabinoids, Cannabidivarin (CBDV) and Cannabidiol (CBD), Activate and Desensitize Transient Receptor Potential Vanilloid 1 (TRPV1) Channels in Vitro: Potential for the Treatment of Neuronal Hyperexcitability

Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. Since the two nonpsychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in hippocampal brain slices exposed to a Mg²⁺-free solution using multielectrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV antiepileptiform effects in the Mg²⁺-free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg²⁺-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy