Sintesi e valutazione biologica di carbossammidi pirazoliche tricicliche contenenti cicloalchili quali nuovi ligandi cannabinergici

Cannabinoid receptor ligands are potential candidates for the therapy of chronic pain, neuroinflammatory diseases, cancer and obesity. In preceding studies the relevance and structure-activity relationships (SAR) of pyrazole derivatives have been consolidated and clarified, and in the process three series of tricyclic compounds as 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazoles, 4,5-dihydro-1H-benzo[g]indazoles and 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent cannabinoid receptor ligands. In the present study five new series of 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl, cyclopentyl or cycloexyl substituent were designed and synthesized to evaluate their affinities towards CB1 and CB2 receptors. Among these derivatives, compound 38Am, exibits a high affinity for CB2 receptor (Ki = 4.48nM) together with remarkable selectivity (KiCB1/KiCB1 = 2232). It is interesting to note, in a in vitro neuroinflammatory test, that compound 3Am shows antagonist activity. Unexpectedly, compound 38Aa possess a agonistic biological profile

The Oxidative state of LDL is the major determinant of anti/prooxidant effect of coffee on Cu²⁺ catalysed peroxidation

Antioxidants exert contrasting effect on low density lipoprotein (LDL) oxidation catalysed by metals, acting as pro-oxidants under select in vitro conditions. Through our study on the effect of coffee on LDL oxidation, we identified the parameters governing this phenomenon, contributing to the comprehension of its mechanism and discovering significant implications for correct alimentary recommendations. By measuring conjugated diene formation, we have analysed the quantitative and qualitative effects exerted by an extract of roasted coffee on LDL oxidation triggered by copper sulphate. When the relative effects of different coffee concentrations were plotted against the lag time (LT) of control LDL (C-LDL), the apparently random experimental data arranged in sensible patterns: by increasing the LT the antioxidant activity of coffee decreased progressively to become prooxidant. The critical LT, at which coffee switches from antioxidant to prooxidant, increased by increasing coffee concentration. Also the contrasting results obtained following a delayed addition of coffee to the assay, arranged in a simple pattern when referred to the LT of C-LDL: the prooxidant effect decreased to become antioxidant as the LT of C-LDL increased. The dependence of coffee effect on the LT of C-LDL was influenced by LDL but not by metal catalyst concentration. These novel findings point to the oxidative state of LDL as a major parameter controlling the anti/prooxidant effect of coffee and suggest the LT of C-LDL as a potent analytical tool to express experimental data when studying the action exerted by a compound on LDL oxidation

The Impact on Survival and Morbidity of Portal-Mesenteric Resection During Pancreaticoduodenectomy for Pancreatic Head Adenocarcinoma. A Systematic Review and Meta-Analysis of Comparative Studies

Background: The literature is conflicting regarding oncological outcome and morbidity associated to portal-mesenteric resection during pancreaticoduodenectomy (PD) in patients with pancreatic head adenocarcinoma (PHAC). Methods: A meta-analysis of studies comparing PD plus venous resection (PD+VR) and standard PD exclusively in patients with adenocarcinoma of the pancreatic head was conducted. Results: Twenty-three cohort studies were identified, which included 6037 patients, of which 28.6% underwent PD+VR and 71.4% underwent standard PD. Patients who received PD+VR had lower 1-year overall survival (OS) (odds radio OR 0.79, 95% CI 0.67-0.92, p = 0.003), 3-year OS (OR 0.72, 95% CI 0.59-0.87, p = 0.0006), and 5-year OS (OR 0.57, 95% CI 0.39-0.83, p = 0.003). Patients in the PD+VR group were more likely to have a larger tumor size (MD 3.87, 95% CI 1.75 to 5.99, p = 0.0003), positive lymph nodes (OR 1.24, 95% CI 1.06-1.45, p = 0.007), and R1 resection (OR 1.74, 95% CI 1.37-2.20, p < 0.0001). Thirty-day mortality was higher in the PD+VR group (OR 1.93, 95% CI 1.28-2.91, p = 0.002), while no differences between groups were observed in rates of total complications (OR 1.07, 95% CI, 0.81-1.41, p = 0.65). Conclusions: Although PD+VR has significantly increased the resection rate in patients with PHAC, it has inferior survival outcomes and higher 30-day mortality when compared with standard PD, whereas postoperative morbidity rates are similar. Further research is needed to evaluate the role of PD+VR in the context of multimodality treatment of PHAC

The Oxidative State of LDL is the Major Determinant of Anti/Prooxidant Effect of Coffee on Cu2+ Catalysed Peroxidation

Antioxidants exert contrasting effect on low density lipoprotein (LDL) oxidation catalysed by metals, acting as pro-oxidants under select in vitro conditions. Through our study on the effect of coffee on LDL oxidation, we identified the parameters governing this phenomenon, contributing to the comprehension of its mechanism and discovering significant implications for correct alimentary recommendations. By measuring conjugated diene formation, we have analysed the quantitative and qualitative effects exerted by an extract of roasted coffee on LDL oxidation triggered by copper sulphate. When the relative effects of different coffee concentrations were plotted against the lag time (LT) of control LDL (C-LDL), the apparently random experimental data arranged in sensible patterns: by increasing the LT the antioxidant activity of coffee decreased progressively to become prooxidant. The critical LT, at which coffee switches from antioxidant to prooxidant, increased by increasing coffee concentration. Also the contrasting results obtained following a delayed addition of coffee to the assay, arranged in a simple pattern when referred to the LT of C-LDL: the prooxidant effect decreased to become antioxidant as the LT of C-LDL increased. The dependence of coffee effect on the LT of C-LDL was influenced by LDL but not by metal catalyst concentration. These novel findings point to the oxidative state of LDL as a major parameter controlling the anti/prooxidant effect of coffee and suggest the LT of C-LDL as a potent analytical tool to express experimental data when studying the action exerted by a compound on LDL oxidation

Tidal notches in Mediterranean Sea: a comprehensive analysis

Recent works (Evelpidou et al., 2012) suggest that the modern tidal notch is disappearing worldwide due sea level rise over the last century. In order to assess this hypothesis, we measured modern tidal notches in several of sites along the Mediterranean coasts. We report observations on tidal notches cut along carbonate coasts from 73 sites from Italy, France, Croatia, Montenegro, Greece, Malta and Spain, plus additional observations carried outside the Mediterranean. At each site, we measured notch width and depth, and we described the characteristics of the biological rim at the base of the notch. We correlated these parameters with wave energy, tide gauge datasets and rock lithology. Our results suggest that, considering \u2018the development of tidal notches the consequence of midlittoral bioerosion\u2019 (as done in Evelpidou et al., 2012) is a simplification that can lead to misleading results, such as stating that notches are disappearing. Important roles in notch formation can be also played by wave action, rate of karst dissolution, salt weathering and wetting and drying cycles. Of course notch formation can be augmented and favoured also by bioerosion which can, in particular cases, be the main process of notch formation and development. Our dataset shows that notches are carved by an ensemble rather than by a single process, both today and in the past, and that it is difficult, if not impossible, to disentangle them and establish which one is prevailing. We therefore show that tidal notches are still forming, challenging the hypothesis that sea level rise has drowned them

Depression in Diabetic Patients: What Is the Link With Eating Disorders? Results of a Study in a Representative Sample of Patients With Type 1 Diabetes

Comorbidity between diabetes and depression, and diabetes and eating disorders (ED) conveys significant diagnostic, clinical and therapeutic implications. The present study was conducted on a sample of adult outpatients affected by Type 1 Diabetes (T1DM) to assess lifetime prevalence of ED; current prevalence of depression and Disturbed Eating Behaviors (DEB) and their impact on glycemic control. We hypothesized that patients with depression would have higher rates of lifetime ED and current DEB. We hypothesized a significant and independent association between DEB and the prevalence of depression

Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models

Acknowledgements The authors acknowledge the contributions of Bettina Seelhorst (histological analysis), Anna Thoma (animal care), Marlene Arthur (animal dosing) and Pierre-Henri Moreau (experimental discussions). This work was supported by TauRx Therapeutics Ltd., Singapore.Peer reviewedPublisher PD

Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1

Peer reviewedPublisher PD

Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with "exemplary phenotypes"-those whose clinical features are reliably associated with LiR and non-response (LiNR)-are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a "clinical exemplar score," which measures the degree to which a subject's clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the "best clinical exemplars") were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the "poor clinical exemplars"). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer's amyloid-secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers