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Lenneke Schrier, Rob Zuiker, Frans W H M Merkus, Erica S Klaassen, Zheng Guan, Bert Tuk, Joop M A van Gerven, Ronald van der Geest, Geert Jan Groeneveld
AIM: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. METHODS: In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and α-hydroxy-midazolam were characterized and related to outcome variables for sedation (Saccadic Peak Velocity, the Bond and Lader Visual Analogue Scale for sedation, the Simple Reaction Time Task and the Observer's Assessment of Alertness/Sedation)...
October 25, 2016: British Journal of Clinical Pharmacology
Hyunho Noh, Yuexing Cui, Aaron W Peters, Dale R Pahls, Manuel A Ortuño, Nicolaas A Vermeulen, Christopher J Cramer, Laura Gagliardi, Joseph T Hupp, Omar K Farha
Molybdenum(VI) oxide was deposited on the Zr6 node of the mesoporous metal-organic framework NU-1000 via condensed-phase deposition where the MOF is simply submerged in the precursor solution, a process named solvothermal deposition in MOFs (SIM). Exposure to oxygen leads to a monodisperse, porous heterogeneous catalyst, named Mo-SIM, and its structure on the node was elucidated both computationally and spectroscopically. The catalytic activity of Mo-SIM was tested for the epoxidation of cyclohexene. Near-quantitative yields of cyclohexene oxide and the ring-opened 1,2-cyclohexanediol were observed, indicating activity significantly higher than that of molybdenum(VI) oxide powder and comparable to that of a zirconia-supported analogue (Mo-ZrO2) prepared in a similar fashion...
October 25, 2016: Journal of the American Chemical Society
Ross S Firestone, Scott A Cameron, Peter C Tyler, Rodrigo Gay Ducati, Adam Z Spitz, Vern L Schramm
5'-Methylthioadenosine phosphorylase (MTAP) and 5'-methylthioadenosine nucleosidase (MTAN) catalyze the phosphorolysis and hydrolysis of 5'-methylthioadenosine (MTA), respectively. Both enzymes have low KM values for their substrates. Kinetic assays for these enzymes are challenging, as the ultraviolet absorbance spectra for reactant MTA and product adenine are similar. We report a new assay using 2-amino-5'-methylthioadenosine (2AMTA) as an alternative substrate for MTAP and MTAN enzymes. Hydrolysis or phosphorolysis of 2AMTA forms 2,6-diaminopurine, a fluorescent and easily quantitated product...
October 25, 2016: Analytical Chemistry
Soji Shimizu
Subporphyrinato boron (subporphyrin) was elusive until the syntheses of tribenzosubporphine in 2006 and meso-aryl-substituted subporphyrin in 2007. These novel contracted analogues possess a 14π-electron conjugated system embedded in a bowl-shaped structure. They exhibit absorption and fluorescence in the UV/vis region and nonlinear optical properties due to their octupolar structures. The unique coordination geometry around the central boron atom in the structure of subporphyrin enabled investigation of rare boron species, such as borenium cations, boron hydrides, and boron peroxides...
October 25, 2016: Chemical Reviews
Ragnhild Undseth, Arnold Berstad, Jørgen Valeur
Irritable bowel syndrome (IBS) is often accompanied by extra‑intestinal symptoms, including fatigue and musculoskeletal pain. The present study aimed to investigate whether these symptoms were associated with markers of enterocyte disintegrity, endotoxemia and inflammation. Patients with IBS were recruited consecutively from our outpatient clinic (n=94) and compared with a group of healthy controls (n=20). Habitual symptoms were assessed using the IBS Severity Scoring System, the Fatigue Impact Scale and Visual Analogue Scales for measuring musculoskeletal pain...
October 21, 2016: Molecular Medicine Reports
Annelies Cannaert, Jolien Storme, Florian Franz, Volker Auwärter, Christophe P Stove
Synthetic cannabinoids (SCs) are the largest group of compounds currently monitored in Europe by the EU Early Warning System on new psychoactive substances. Emerging recreational use of these products has led to multiple cases of adverse health effects and even death. In contrast to marijuana, where Δ9-tetrahydrocannabinol (Δ9THC) is metabolized to only one major active metabolite, it has been reported that several major phase I metabolites of SCs remain biologically active, exerting cannabinoid (CB) receptor affinity, potency and efficacy greater than Δ9THC...
October 25, 2016: Analytical Chemistry
Bethany G Caulkins, Robert P Young, Ryan A Kudla, Chen Yang, Thomas J Bittbauer, Baback Bastin, Eduardo Hilario, Li Fan, Michael J Marsella, Michael F Dunn, Leonard J Mueller
Carbanionic intermediates play a central role in the catalytic transformations of amino acids performed by pyridoxal-5'-phosphate (PLP)-dependent enzymes. Here, we make use of NMR crystallography - the synergistic combination of solid-state nuclear magnetic resonance, X-ray crystallography, and computational chemistry - to interrogate a carbanionic/quinonoid intermediate analogue in the β-subunit active site of the PLP-requiring enzyme tryptophan synthase. The solid-state NMR chemical shifts of the PLP pyridine ring nitrogen and additional sites, coupled with first principles computational models, allow a detailed model of protonation states for ionizable groups on the cofactor, substrates, and nearby catalytic residues to be established...
October 25, 2016: Journal of the American Chemical Society
Jennifer A Ward, Lauren McLellan, Martin Stockley, Karl R Gibson, Gavin A Whitlock, Charlotte Knights, Jeanine A Harrigan, Xavier Jacq, Edward W Tate
Deubiquitinating enzymes play an important role in a plethora of therapeutically relevant processes, and are emerging as pioneering drug targets. Herein, we present a novel probe Ubiquitin Specific Protease (USP) inhibitor, alongside an alkyne-tagged activity-based probe analogue. Activity-based proteome profiling identified 12 USPs, including USP4, USP16, and USP33, as inhibitor targets using sub-micromolar probe concentrations. This represents the first intact cell activity-based profiling of deubiquitinating enzymes...
October 25, 2016: ACS Chemical Biology
Pengfei Li, Jindian Duan, Yuyu Cheng, Jing Cheng, Rou Li
A new method has been developed for the organocatalytic enantioselective benzylation and aldol-hemiacetalization of α,β-unsaturated trifluoromethyl ketones with toluene derivatives in the presence of a tertiary amine-thiourea catalyst. This method represents a facile and efficient strategy for the asymmetric synthesis of optically active 3,4-dihydroisocoumarins bearing a trifluoromethylated tetrasubstituted carbon stereocenter with high enantioselectivity. Notably, this strategy was used to synthesize several chiral trifluoromethylated analogues of typharin with high efficiency...
October 25, 2016: Chemistry: a European Journal
K Nakamura, C J Brainerd
It has recently been found that episodic memory displays analogues of the well-known disjunction and conjunction fallacies of probability judgement. The aim of the present research was, for the first time, to study these memory fallacies together under the same conditions, and test theoretical predictions about the reasons for each. The focus was on predictions about the influence of semantic gist, target versus context recollection, and proactive versus retroactive interference. Disjunction and conjunction fallacies increased in conditions in which subjects were able to form semantic connections among list words...
October 25, 2016: Memory
Bing Yang, Xin Ming, Hajer Abdelkafi, Valerie Pons, Aurelien Michau, Daniel Gillet, Jean-Christophe Cintrat, Julien Barbier, Rudy Juliano
Retro-1 is a small molecule that displays two important biological activities: First, it blocks the actions of certain toxins by altering their intracellular trafficking. Second, it enhances the activity of oligonucleotides by releasing them from entrapment in endosomes. This raises the question of whether the two actions involve the same cellular target. Herein we report the effects of several Retro-1 analogues on both toxins and oligonucleotides. We found analogues that affect toxins but not oligonucleotides and vice-versa, while Retro-1 is the only compound that affects both...
October 25, 2016: ChemMedChem
Kaweh Mansouri, Tarek Shaarawy
PURPOSE: To compare safety, tolerability and intraocular pressure (IOP)-lowering efficacy of pattern scanning laser trabeculoplasty (PSLT) with selective laser trabeculoplasty (SLT) in fellow eyes of untreated patients with glaucoma. DESIGN: Randomized controlled trial. PARTICIPANTS: Twenty-nine patients (58 eyes) with primary and secondary open angle glaucoma (OAG) were randomized to undergo PSLT or SLT in each eye. METHODS: Pattern scanning laser trabeculoplasty was performed using the Pascal laser (Pascal Streamline 577; Topcon Inc...
October 25, 2016: Acta Ophthalmologica
Dawid Lichosyt, Paweł Dydio, Janusz Jurczak
Herein we report the synthesis and detailed studies of the anion-binding properties of two 20-membered macrocyclic tetramide receptors: one symmetrical, containing two identical azulene-based bisamide units, the other a hybrid, containing a dipicolinic bisamide unit and an azulene-based bisamide unit. Analysis of the crystal structures of the macrocyclic receptors revealed their preference for adopting similar well-preorganized bent-sheet conformations, both as free receptors and in their complexes with anions...
October 25, 2016: Chemistry: a European Journal
Brian F Kiesel, Robert A Parise, Jianxia Guo, Donna M Huryn, Paul A Johnston, Raffaele Colombo, Malabika Sen, Jennifer R Grandis, Jan H Beumer, Julie L Eiseman
PURPOSE: The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) promotes gene transcription involved in cancer, and its activation by IL-6 is found in head and neck squamous cell carcinoma. Four triazolothiadizine STAT3 pathway inhibitors were evaluated to prioritize a single compound for in vivo examination. METHODS: Metabolic stability in mouse liver microsome incubation was used to evaluate four triazolothiadizine analogues, and UPCDC-10205 was administered to mice IV as single or multiple doses to evaluate toxicity...
October 24, 2016: Cancer Chemotherapy and Pharmacology
Min-Seon Choi, Eun-Young Kim
PURPOSE: Precocious puberty (PP) is associated with psychological and behavioral problems. This study aimed to evaluate the perception of body image and depression in girls with PP receiving gonadotropin-releasing hormone (GnRH) analogue therapy. METHODS: From March to August 2013, 82 girls with PP receiving GnRH analogue therapy were enrolled. Height, weight, body mass index, and stages of pubertal development were assessed. Participants completed a series of questionnaires on their body image perception and pubertal self-assessment...
September 2016: Annals of Pediatric Endocrinology & Metabolism
Peter E Ghaly, Rabab M Abou El-Magd, Cassandra D M Churchill, Jack A Tuszynski, F G West
Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound...
June 28, 2016: Oncotarget
Jing Ke, Rui Wei, Fei Yu, Jingjing Zhang, Tianpei Hong
Glucagon-like peptide-1 (GLP-1) and its analogues have a beneficial role in cardiovascular system. Here, we aimed to investigate whether liraglutide, a GLP-1 analogue, modulated angiogenesis impaired by palmitic acid (PA) in cultured human umbilical vein endothelial cells (HUVECs). Cells were incubated with liraglutide (3-100 nmol/L) in the presence of PA (0.5mmol/L), and endothelial tube formation was observed and quantified. The protein levels of signaling molecules were analyzed and the specific inhibitors were used to identify the signaling pathways through which liraglutide affected angiogenesis...
October 21, 2016: Peptides
C Parkinson, P Constantin, C Goyal, C Hall
OBJECTIVES: This study aimed to investigate whether addition of an octadecene/maleic anhydride copolymer (O/MA) to a potassium nitrate (KNO3) dentifrice could facilitate delivery of potassium to dentine and enhance its efficacy in dentine hypersensitivity relief. METHODS: This was a randomised, examiner-blind, controlled, parallel group study in 139 healthy subjects with at ≥2 sensitive teeth. Assessment of dentine hypersensitivity to tactile (Yeaple probe) and evaporative (air) stimuli (Schiff Sensitivity Scale, visual analogue scale [VAS]) was carried out at baseline and after 1, 2, 4 and 8 weeks twice daily treatment with an experimental 5% KNO3/3% O/MA dentifrice, a comparator 5% KNO3 dentifrice (active comparator), a 0% KNO3/3% O/MA dentifrice (placebo) and a regular fluoride dentifrice (negative control)...
October 21, 2016: Journal of Dentistry
Olympia Koulouri, Andrew C Hoole, Patrick English, Kieren Allinson, Nagui Antoun, Heok Cheow, Neil G Burnet, Neil Donnelly, Richard J Mannion, Mark Gurnell
No abstract text is available yet for this article.
October 21, 2016: Lancet Diabetes & Endocrinology
Min Wang, Shan Xu, Chunjiang Wu, Xiaobo Liu, Hong Tao, Yanli Huang, Yongchan Liu, Pengwu Zheng, Wufu Zhu
Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a-o, 7a-e) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC50 values of 0...
October 12, 2016: Bioorganic & Medicinal Chemistry Letters
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