Gene Expression Profiling of Peri-Implant Healing of PLGA-Li+ Implants Suggests an Activated Wnt Signaling Pathway In Vivo

Bone development and regeneration is associated with the Wnt signaling pathway that, according to literature, can be modulated by lithium ions (Li+). The aim of this study was to evaluate the gene expression profile during peri-implant healing of poly(lactic-co-glycolic acid) (PLGA) implants with incorporated Li+, while PLGA without Li+ was used as control, and a special attention was then paid to the Wnt signaling pathway. The implants were inserted in rat tibia for 7 or 28 days and the gene expression profile was investigated using a genome-wide microarray analysis. The results were verified by qPCR and immunohistochemistry. Histomorphometry was used to evaluate the possible effect of Li+ on bone regeneration. The microarray analysis revealed a large number of significantly differentially regulated genes over time within the two implant groups. The Wnt signaling pathway was significantly affected by Li+, with approximately 34% of all Wnt-related markers regulated over time, compared to 22% for non-Li+ containing (control; Ctrl) implants. Functional cluster analysis indicated skeletal system morphogenesis, cartilage development and condensation as related to Li+. The downstream Wnt target gene, FOSL1, and the extracellular protein-encoding gene, ASPN, were significantly upregulated by Li+ compared with Ctrl. The presence of beta-catenin, FOSL1 and ASPN positive cells was confirmed around implants of both groups. Interestingly, a significantly reduced bone area was observed over time around both implant groups. The presence of periostin and calcitonin receptor-positive cells was observed at both time points. This study is to the best of the authors' knowledge the first report evaluating the effect of a local release of Li+ from PLGA at the fracture site. The present study shows that during the current time frame and with the present dose of Li+ in PLGA implants, Li+ is not an enhancer of early bone growth, although it affects the Wnt signaling pathway

Chemical synthesis, characterisation and in vitro and in vivo metabolism of the synthetic opioid MT-45 and its newly identified fluorinated analogue 2F-MT-45 with metabolite confirmation in urine samples from known drug users

© 2018 The Author(s) Purpose: The detection of a novel psychoactive substance, 2F-MT-45, a fluorinated analogue of the synthetic opioid MT-45, was reported in a single seized tablet. MT-45, 2F-, 3F- and 4F-MT-45 were synthesised and reference analytical data were reported. The in vitro and in vivo metabolisms of MT-45 and 2F-MT-45 were investigated. Method: The reference standards and seized sample were characterised using nuclear magnetic resonance spectroscopy, ultra-performance liquid chromatography–quadrupole time of flight mass spectrometry, gas chromatography–mass spectrometry, attenuated total reflectance-Fourier transform infrared spectroscopy and Raman spectroscopy. Presumptive tests were performed and physicochemical properties of the compounds determined. Metabolite identification studies using human liver microsomes, human hepatocytes, mouse hepatocytes and in vivo testing using mice were performed and identified MT-45 metabolites were confirmed in authentic human urine samples. Results: Metabolic pathways identified for MT-45 and 2F-MT-45 were N-dealkylation, hydroxylation and subsequent glucuronidation. The major MT-45 metabolites identified in human in vitro studies and in authenticated human urine were phase I metabolites and should be incorporated as analytical targets to existing toxicological screening methods. Phase II glucuronidated metabolites were present in much lower proportions. Conclusions: 2F-MT-45 has been detected in a seized tablet for the first time. The metabolite identification data provide useful urinary metabolite targets for forensic and clinical testing for MT-45 and allows screening of urine for 2F-MT-45 and its major metabolites to determine its prevalence in case work

Hedgefonders investeringsstrategier och överavkastning

Hedgefonders investeringsstrategier och överavkastning En hedgefond är en fond med ett avkastningsmål som är absolut och oberoende av marknadsriktning då förvaltaren inte jämför hedgefondens avkastning med ett index. Denna typ av fond har vanligtvis stor flexibilitet i förvaltningsinriktningen, de kan använda sig av såväl långa som korta positioner samt utnyttja belåning och derivat för att ytterligare öka avkastningen. Hedgefonder har under 1990-talet växt kraftigt och som en följd av detta har hedgefonder blivit intressanta som studieobjekt för akademiska undersökningar och forskning. Intressant ur en investerares synpunkt är att studera om hedgefonder kan påvisa signifikanta överavkastningar. Vi fokuserar på fondernas avkastning i relation till vilken investeringsstrategi som fonden har valt och utvärderar fonderas prestationer med hjälp av tre ekonomiska modeller; CAPM, Fama-Frenchs trefaktormodell samt en betingad trefaktormodell. Våra resultat visar på positiva, signifikanta alfavärden för de olika investeringsstrategierna. Sålunda kan vi visa att de åtta undersökta investeringsstrategierna presterat bättre än vad som kan förklaras med hjälp av gängse modeller. Resultaten för de enskilda alfavärdena skiljer sig mellan modellerna och några entydiga resultat om någon strategis överlägsenhet över någon annan är svår att dra