Novel ligands directly enhancing the endocannabinoid system: design and synthesis of new N-(2-oxo-1,2-dihydropyridin-3-yl)cycloheptanecarboxamide derivatives

The endocannabinoid system is now known to be an ubiquitous neuromodulatory system with wide-ranging actions. It consists of endogenous cannabinoids (endocannabinoids), cannabinoid receptors and synthetic and degrading enzymes responsible for synthesis and degradation of endocannabinoids. Endocannabinoids (EC) are lipid messengers derivatives of integral components of the cellular membranes: anandamide and 2-arachidonoylglycerol are the best characterized. Their levels are maintained mainly by two catabolic enzymes: the fatty acid amide hydrolase (FAAH) and the monoacylglyceride lipase (MAGL). Cannabinoid receptors 1 and 2 (CB1 and CB2) belong to the superfamily of G-protein-coupled receptors. CB1 receptor is predominant in the central nervous system while CB2 receptor is located mainly in immune cells, such as macrophages, microglia, and B and T cells. As CB1 receptor mediates most, if not all, of the psychoactive effects of cannabinoids, CB2 receptor selective ligands are attractive as therapeutics because they would presumably lack this psychoactivity. Therefore, therapeutic strategies might include the use of cannabinoid receptor agonists and/or antagonists, but also the blockage of hydrolytic enzymes degrading ECs, the inhibition of EC transporters (EMT) and the inhibition of EC uptake. However, the current comprehension of the complexity of the endocannabinoid system seems to indicate a need of multitarget drugs, which exert their pro-cannabinoid activities by means of more than one mechanism of action. In fact, these molecules could offer the advantage of modulating the ECS in a safer and more therapeutically efficacious way. In a previous research program aimed to obtain CB2 receptor selective ligands, a new series of 2-oxo-1,2-dihydropyridine-3-carboxamide derivatives which showed high CB2 receptor affinity and selectivity, were individuated. Furthermore, the introduction of a substituent in position 5 of the heterocyclic nucleus showed an interesting effect on the activity on the CB2 receptor. Indeed, the nature of this substituent determined the control of the switch among the different types of pharmacological modulation: agonism, inverse agonism or antagonism on the receptor. Subsequently the 5-substituted 2-oxo-1,2-dihydropyridine-3-carboxamide derivatives were modified through the insertion of a methyl group at the positions C4 or C6 These compounds were tested in order to evaluate the influence of a small substituent at the position 4 or 6 of the heterocyclic nucleus on the CBR affinity. The compounds of both series showed not only the best binding properties at CB2 receptors, but also the same behaviour towards these receptors. Furthermore, the 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives showed also to be inhibitors of AEA and 2-AG uptake with EC50 values in the nM range for some of them. Finally, some of these ligands showed to inhibit the fatty acid amide hydrolase (FAAH). In the light of these good results, with the aim to deepen the structure activity relationship (SAR) of this series of compounds, during my thesis work, the N-(2-oxo-1,2-dihydropyridin-3-yl)cycloheptanecarboxamide derivatives were designed and synthesized as analogs of previous compounds in which the amide group in position C3 was substituted by the corresponding reverse amide

Marine bivalve feeding strategies and radiocarbon ages in Northeast Atlantic coastal waters

Authors acknowledge the support of NERC and an award to WA through the RAPID program (project NE/C000137/1).Marine mollusk shells have been extensively used to provide radiocarbon (14C)-based chronologies in paleoenvironmental and archaeological studies, however uncertainties in age measurements are introduced because secondary factors such as vital effects and diet may influence 14C incorporation into these shells. Deep burrowing and deposit feeding mollusks, in particular, may incorporate “old” carbon resulting in apparently older ages than their contemporary environment. In this study, we present paired 14C and stable isotope (δ13C and δ18O) measurements for nine species of known-age bivalves having different feeding strategies and collected in six localities around the NE Atlantic. We exclude potential “old” carbon contamination in these known-age mollusk shells, acquire a better understanding of local ecology and provide an improved context for the environmental interpretation of 14C ages. Our results indicate that, in the NE Atlantic, marine mollusk-derived 14C ages provide a reliable basis for environmental and archaeological investigation, independently of vital effects and differences in microhabitats, feeding strategies and sample location—all of which are apparent from stable isotopes.PostprintPeer reviewe

Late Pleistocene variability in Timor Sea hydrology: evidence from paleotemperature proxies

Since the early days of paleoceanographic investigations, variations in temperature, salinity and other environmental parameters have been reconstructed based on the elemental and isotopic composition of both planktonic and benthic foraminiferal tests deposited in marine sediments. However, substantial uncertainties still exist concerning the relationships between geochemical proxies and ambient variability. In the first phase of this study, I investigated the reliability of geochemical proxies (Mg/Ca and 18O) for bottom water temperature (BWT) and sea surface temperature (SST) reconstructions in a suite of core top samples from the Timor Sea and Makassar Strait. In the second phase of this study, I used a multi-proxy record of planktonic and benthic foraminiferal 18O, Mg/Ca-derived surface and lower thermocline temperatures, X-ray fluorescence (XRF)-derived runoff and sediment winnowing from sediment core SO18471 to reconstruct hydrological variability in the Timor Strait for the past 130 ka

Thyroid Hormone Profile in Patients Ingesting Soft Gel Capsule or Liquid Levothyroxine Formulations with Breakfast

Background. Recently, it has been shown that liquid L-T4 formulation can be ingested with breakfast. This study looked to extend these findings by investigating whether a soft gel capsule formulation of L-T4 could also be ingested at breakfast time. Methods. 60 patients (18–65 yrs), previously submitted to thyroidectomy for proven benign goitre in stable euthyroidism receiving liquid L-T4 therapy ingested with breakfast, were enrolled. TSH, fT4, and fT3 levels were assessed in all the patients who were switched from liquid L-T4 to a soft gel capsule formulation at the same dosage of L-T4. After 6 months, TSH, fT4, and fT3 levels were determined again. Results. There were no differences in TSH levels, but fT3 and fT4 levels during treatment with the soft gel capsule were significantly lower than those at enrolment with the liquid L-T4 formulation (TSH median (min–max): 1.9 (0.5–4.0) versus 2.2 (0.5–4.5) mIU/L, fT3: 2.5 (2.4–3.1) versus 2.7 (2.4–3.3) pg/mL, p<0.05, and fT4: 9.9 (8.0–13) versus 10.6 (8.6–13.8) pg/mL, p<0.0001). Conclusion. Both liquid and soft gel formulations of L-T4 can be taken with breakfast. However, liquid L-T4 would be the preferred formulation for patients in whom even small changes in fT4 and fT3 levels are to be avoided

Size matters : analyses of benthic foraminiferal assemblages across differing size fractions

This project was supported by the BBSRC/NERC (ref. BB/M026620/01).Benthic foraminiferal assemblages are the object of numerous studies spanning from (palaeo)environmental reconstructions to biomonitoring; however, the establishment of a procedure to standardize these studies remains a recent achievement. Not all studies based on benthic foraminiferal assemblages adopt the same methodology, which potentially hinders the use and comparison of samples prepared prior to the creation of a standard protocol or, indeed, without the knowledge of it. One of the main issues is to understand and possibly quantify the influence of different size fractions on foraminiferal biodiversity and richness. In this study, we analyzed benthic foraminiferal assemblages from the west coast of Shetland (Scotland), which were deliberately prepared without following the standard procedure, and were instead picked from the size fractions 63–150 μm and >150 μm. Based on assemblage composition, biodiversity indices and multivariate analyses of the data, we assessed the quality and precision of the environmental information that could be extrapolated from these samples. We found that general biodiversity trends remain the same regardless of size fraction, whereas the assemblage internal composition is significantly different between size fractions, with the small fraction retaining a greater degree of environmental sensitivity. We recommend compiling the two sample sets to produce a more holistic and detailed picture of environmental change and generate high-resolution environmental reconstructions. Nevertheless, we conclude that benthic foraminiferal assemblages picked from the large size fraction (>150 μm) still provide useful information on prevailing environmental conditions and remain useful for an overview of environmental change in these coastal settings.Publisher PDFPeer reviewe

Croatian Liberal Press about Reform Movement of Part of Catholic Lower Clergy (1918—1923)

Kraj Prvog svjetskog rata značio je prekretnicu u hrvatskoj nacionalnoj povijesti. S druge strane Crkva u Hrvata suočila se s pokretom nižeg katoličkog klera koji je zahtijevao poboljšanje svoga materijalnog statusa. Ovaj pokret prerastao je s vremenom u reformni pokret ili tzv. "žuti pokret" koji je u svojim zahtjevima zalazio u crkvenu disciplinu tražeći velike reformske zahvate na tom području. Dok je službeni i poluslužbeni katolički tisak oštro nastupao prema reformnom pokretu liberalni tisak je s neskrivenim simpatijama gledao na sam pokret i otvoreno ga podržavao. Zahtjevi članova reformnog pokreta usko su se podudarali s liberalnim pogledom na Crkvu te su liberalne novine toga vremena veliki prostor davali reformaπima i njihovim zahtjevima. Ovo otvoreno podržavanje reformnog pokreta od strane hrvatskog liberalnog tiska bilo je neupitno sve do donošenja Vidovdanskog ustava u lipnju 1921. godine. Zbog potpore koju je pokret uživao od strane tiska bliskog Pribićevićevoj Samostalnoj demokratskoj stranci hrvatski liberalni tisak potpuno mijenja svoj odnos prema reformnom pokretu. Od otvorene podrške na njega se sada gleda kao produženu ruku beogradske vlade kojom se želi oslabiti hrvatski nacionalni korpus, u kojem katolicizam ima bitnu ulogu. Osnivanje Hrvatske starokatoličke crkve krajem 1923. godine liberalni tisak popratiti će poprilično nezainteresirano.The end of First World War was turning-point of in Croatian national history. Catholic Church in Croatia was in this period confronted with movement of part of lower clergy which had demanded improvement of his material status. This movement had become Reform movement also called flYellow movement« which had in his demands frequenting deep in the discipline maters of Catholic Church. Demands of Reform movement had correspond with liberal view on Church maters so Croatian liberal press of that time had given to the movement his full support. This support of Croatian liberal press to the Reform movement was strong until the June 1921 when the Vidovdan Constitution was voted. Because of support which Reform movement had from Pribičević’s Independent Democratic Party Croatian liberal press completely changes his attitude to movement. From strong support they now write about Reform movement like extended hand of Belgrade government for languishment of Croatian national being, in which Catholic Church had strong position. About foundation of Croatian Old Catholic Church at the end of 1923 liberal press will wrote with indifference

A case of central venous catheter-related Candida parapsilosis fungemia evolved to disseminated infection in a neutropenic patient with blast crisis of chronic myeloid leukemia.

Central venous catheter-related infections are of particular importance in onco-hematological patients. Candida parapsilosis is generally reported as a mild pathogen, however it is able to effectively colonize intravascular devices and potentially give rise to sustained fungemias. Here we report a case of invasive, potentially lethal C. parapsilosis disseminated infection in a neutropenic patient affected by chronic myeloid leukemia with blast crisis. We underline the importance of removing the central venous catheter as potential source of infection as soon as possible during the course of candidemia, and not replacing it with other polyurethan intravascular devices, which pose a risk for the maintenance of the fungemia despite the administration of the best antifungal therapy available