738 research outputs found

    Beta2-adrenergic ligand racemic formoterol exhibits enantioselective disposition in blood and skeletal muscle of humans, and elicits myocellular protein kinase A-signalling at therapeutic inhaled doses

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    While studies have demonstrated substantial differences in beta2-adrenergic agonist enantiomer pharmacology, enantioselective disposition of long-acting beta2-adrenergic ligand racemic (rac)-formoterol in blood is unexplored after inhaled therapy given analytical challenges. Furthermore, information on enantioselective disposition and partitioning of beta2 -adrenergic agonist in skeletal muscle is absent despite its promising data on muscle anabolism in humans. Using a sensitive UPLC-MS/MS (ultra-high performance liquid chromatography-mass spectrometry) assay, we determined disposition of (R,R)-formoterol and (S,S)-formoterol in plasma and skeletal muscle samples from 11 non-asthmatic men who had inhaled rac-formoterol at therapeutic doses (2×27 μg). Mean (SD) concentrations of (R,R)- and (S,S)-formoterol in plasma and in muscle biopsies of the vastus lateralis 1 h after inhalation of formoterol were 31 (15) and 45 (18) pg×mL-1 for (R,R)-formoterol and (S,S)-formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pg×mgwet wt-1, respectively, in muscle. Formoterol exhibited different enantioselective disposition in plasma and muscle (p R,R):(S,S)-formoterol ratio was lower than 0 [-0.17(0.07), p R,R):(S,S)-formoterol ratio was slightly higher than 0 [0.04(0.07), p R,R):(S,S)-formoterol ratio in muscle was related to muscle fibre-type composition. Furthermore, formoterol induced an approximately two-fold increase in muscle p-PKASer/thr phosphorylation (p 2 -adrenergic response. Collectively, these findings suggest that formoterol exhibits modest enantioselective disposition in plasma after inhaled therapy in humans, which appear related to a greater (R,R)-enantiomer disposition in skeletal muscle that may be dependent on fibre-type composition

    MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors

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    BACKGROUND MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers

    Heavy metals burden of Keenjhar Lake, District Thatta, Sindh, Pakistan

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    Detection of heavy metals (HMs) content from Keenjhar Lake water was carried out monthly from January to December, 2003. Zinc, chromium, copper, iron, manganese, nickel and cadmium were analyzed by dual mode of analytical methods flame atomic absorption spectrometry and electrothermal atomic absorption spectrometry (FAAS and ETAAS) by multi element standard solution. The concentrations of zinc, chromium, copper, iron, manganese Nickel and cadmium were 1.4 to 104.3 μgL-1, 1.28 to 4.9 μgL-1, 0.6 to 7.3 μgL-1, 2 to 45.6 μgL-1, 0.2 to 6.7 μgL-1, 3.54 to 39.5 μgL-1 and 1.0 to 4.3 μgL-1, respectively. Zn2+, Cr+, Cu2+, Fe2+ and Mn2+ concentrations were recorded lower than those of permissible limits, whereas Ni+ and Cd+ were higher than those of permissible limits recommended by WHO (2004).Key words: Heavy metals, Keenjhar Lake, toxicity

    Search for new physics in the multijet and missing transverse momentum final state in proton-proton collisions at √s=8 Tev

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    Measurement of Higgs boson production and properties in the WW decay channel with leptonic final states

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    Study of double parton scattering using W+2-jet events in proton-proton collisions at √s=7 TeV

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    Prosthetic valve endocarditis caused by Staphylococcus capitis: report of 4 cases

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    Although Staphylococcus capitis is considered to be a rare causative organism for prosthetic valve endocarditis, we report 4 such cases that were encountered at our hospital over the past 2 years. Case 1 was a 79-year-old woman who underwent aortic valve replacement with a bioprosthetic valve and presented with fever 24 days later. Transesophageal echocardiography revealed an annular abscess in the aorto-mitral continuity and mild perivalvular regurgitation. We performed emergency surgery 5 days after the diagnosis of prosthetic valve endocarditis was made. Case 2 was a 79-year-old woman presenting with fever 40 days after aortic valve replacement with a bioprosthesis. Transesophageal echocardiography showed vegetation on the valve, and she underwent urgent surgery 2 days after prosthetic valve endocarditis was diagnosed. In case 3, a 76-year-old man presented with fever 53 days after aortic valve replacement with a bioprosthesis. Vegetation on the prosthetic leaflet could be seen by transesophageal echocardiography. He underwent emergency surgery 2 days after the diagnosis of prosthetic valve endocarditis was made. Case 4 was a 68-year-old woman who collapsed at her home 106 days after aortic and mitral valve replacement with bioprosthetic valves. Percutaneous cardiopulmonary support was started immediately after massive mitral regurgitation due to prosthetic valve detachment was revealed by transesophageal echocardiography. She was transferred to our hospital by helicopter and received surgery immediately on arrival. In all cases, we re-implanted another bioprosthesis after removal of the infected valve and annular debridement. All patients recovered without severe complications after 2 months of antibiotic treatment, and none experienced re-infection during 163 to 630 days of observation. Since the time interval between diagnosis of prosthetic valve endocarditis and valve re-replacement ranged from 0 to 5 days, early surgical removal of the infected prosthesis and an appropriate course of antibiotics were attributed to good clinical outcomes in our cases

    Measurements of the tt¯ charge asymmetry using the dilepton decay channel in pp collisions at √s=7 TeV

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