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M4
Terms modified by M4 Selected AbstractsThe importance of independent risk-factors for long-term mortality prediction after cardiac surgeryEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 9 2006I. K. Toumpoulis Abstract Background, The purpose of the present study was to determine independent predictors for long-term mortality after cardiac surgery. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was developed to score in-hospital mortality and recent studies have shown its ability to predict long-term mortality as well. We compared forecasts based on EuroSCORE with other models based on independent predictors. Methods, Medical records of patients with cardiac surgery who were discharged alive (n = 4852) were retrospectively reviewed. Their operative surgical risks were calculated according to EuroSCORE. Patients were randomly divided into two groups: training dataset (n = 3233) and validation dataset (n = 1619). Long-term survival data (mean follow-up 5·1 years) were obtained from the National Death Index. We compared four models: standard EuroSCORE (M1); logistic EuroSCORE (M2); M2 and other preoperative, intra-operative and post-operative selected variables (M3); and selected variables only (M4). M3 and M4 were determined with multivariable Cox regression analysis using the training dataset. Results, The estimated five-year survival rates of the quartiles in compared models in the validation dataset were: 94·5%, 87·8%, 77·1%, 64·9% for M1; 95·1%, 88·0%, 80·5%, 64·4% for M2; 93·4%, 89·4%, 80·8%, 64·1% for M3; and 95·8%, 90·9%, 81·0%, 59·9% for M4. In the four models, the odds of death in the highest-risk quartile was 8·4-, 8·5-, 9·4- and 15·6-fold higher, respectively, than the odds of death in the lowest-risk quartile (P < 0·0001 for all). Conclusions, EuroSCORE is a good predictor of long-term mortality after cardiac surgery. We developed and validated a model using selected preoperative, intra-operative and post-operative variables that has better discriminatory ability. [source] Checking the Route to Cluster HelicatesEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 24 2008Manuel R. Bermejo Abstract The aim of the work described here was to test the general applicability of our recently reported route to cluster helicates and to carry out a systematic study to relate the structural and coordinative properties of the organic strands with the microarchitectures of the resulting cluster helicates. Nine new ZnII, CuI and AgI complexes were prepared from three Schiff base ligands [H2La: bis(4-methyl-3-thiosemicarbazone)-2,6-diacetylpyridine; H2Lb: bis(4-methyl-3-thiosemicarbazone)-2,6-diacetylbenzene; H2Lc: bis(4-ethyl-3-thiosemicarbazone)-2,6-diacetylbenzene]. The experimental data confirm that AgI and CuI tetranuclear cluster helicates were obtained with a [M4(Lx)2] stoichiometry, and this finding demonstrates the general applicability of the synthetic route. The cluster helicates presented in this work were characterized for the first time in solution by NMR spectroscopy. In addition, six of the nine complexes were characterized by X-ray diffraction studies, and three of them were found to be tetranuclear cluster helicates. A detailed study of these three crystal structures leads us to state that the changes introduced in the organic strands do not prevent the assembly of the tetranuclear cluster dihelicates, but they do affect the microarchitectures. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] Highly Symmetrical Tetranuclear Cluster Complexes Supported by p - tert -Butylsulfonylcalix[4]arene as a Cluster-Forming LigandEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 9 2006Takashi Kajiwara Abstract Square-planar tetranuclear clusters [M4(L)(AcO)4(,4 -OH)], (M = MnII, CoII, and NiII) are synthesized using tetra-anionic p - tert -butylsulfonylcalix[4]arene (L4,) as a cluster-forming ligand. Three complexes are crystallographically isostructural, being crystallized in the triclinic crystal system with space group P. The calix[4]arene acts as a tetrakis fac -tridentate ligand through four phenoxo and four sulfonyl oxygen atoms to form square arrangement of four metal ions, which are further bridged by four chelating acetate ions and one hydroxo ion in a ,4 manner to complete the hexacoordination of each metal center. Although the whole molecule of each complex is crystallographically independent, the molecule is highly symmetrical with a pseudo-four-fold axis lying on the ,4 -OH, group. The tetranuclear clusters are stable enough to maintain the core structures even in highly dilute solution (,10 ,M), which was confirmed by mass spectroscopic study, however, bridging acetates were easily exchanged by other carboxylate chelates to form derivatives such as [M4(L)(BzO)4(OH)],. Metal,metal interactions were investigated by means of magnetic susceptibility, and it was revealed that both ferro- and antiferromagnetic interactions occur in the NiII complex depending on the bridging angles of Ni,O,Ni. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] Modulation of ACh release by presynaptic muscarinic autoreceptors in the neuromuscular junction of the newborn and adult ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2003Manel M. Santafé Abstract We studied the presynaptic muscarinic autoreceptor subtypes controlling ACh release and their relationship with voltage-dependent calcium channels in the neuromuscular synapses of the Levator auris longus muscle from adult (30,40 days) and newborn (3,6 and 15 days postnatal) rats. Using intracellular recording, we studied how several muscarinic antagonists affected the evoked endplate potentials. In some experiments we previously incubated the muscle with calcium channel blockers (nitrendipine, ,-conotoxin-GVIA and ,-Agatoxin-IVA) before determining the muscarinic response. In the adult, the M1 receptor-selective antagonist pirenzepine (10 µm) reduced evoked neurotransmission (, 47%). The M2 receptor-selective antagonist methoctramine (1 µm) increased the evoked release (, 67%). Both M1- and M2-mediated mechanisms depend on calcium influx via P/Q-type synaptic channels. We found nothing to indicate the presence of M3 (4-DAMP-sensitive) or M4 (tropicamide-sensitive) receptors in the muscles of adult or newborn rats. In the 3,6-day newborn rats, pirenzepine reduced the evoked release (, 30%) by a mechanism independent of L-, N- and P/Q-type calcium channels, and the M2 antagonist methoctramine (1 µm) unexpectedly decreased the evoked release (, 40%). This methoctramine effect was a P/Q-type calcium-channel-dependent mechanism. However, upon maturation in the first two postnatal weeks, the M2 pathway shifted to perform the calcium-dependent release-inhibitory activity found in the adult. We show that the way in which M1 and M2 muscarinic receptors modulate neurotransmission can differ between the developing and adult rat neuromuscular synapse. [source] The role of the cutaneous cholinergic system in guttate psoriasisEXPERIMENTAL DERMATOLOGY, Issue 7 2008W. Dyck In previous studies, high levels of acetylcholine (ACh) have been reported in psoriasis lesions. In addition, patients with guttate psoriasis respond to oral treatment with atropine. We wanted to know how the cutaneous cholinergic system could be involved in this process. Since mast cells (MC) are characteristic components of the inflammatory infiltrate of guttate psoriasis, we compared ACh receptor (AChR) composition and ACh production in both epidermis and mast cells of 10 patients with guttate psoriasis in involved and uninvolved skin on protein level using immunofluorescence and in a MC line (HMC-1) using PCR. We could confirm the presence of numerous MC in guttate psoriasis lesion. Both in vivo and in vitro, MC lacked expression of cholinacetyltransferase (ChAT), vesicular acetylcholintransorter (VAChT) and cholintransporter-1 (ChT-1) but contained high levels of acetylcholinesterase (AChE). In mast cells of both involved and uninvolved skin we found both nicotinic (,3, ,5, ,7, ,9, ,10, ,2 and ,4 subunits) and muscarinic (M1, M3, M4, M5) AChR. In HMC-1 cells all AChR subunits found in skin where present on mRNA level, except ,7 and ,2. In lesional epidermis both ACh production and AChR expression was shifted from the basal to the suprabasal layers especially the nicotinic ,3, ,5, ,9, ,2 and ,4 and the muscarinic M3 and M5 AChR subunits. Our results exclude a role of the cholinergic system in the initiation of keratinocyte proliferation in the basal epidermal layer but point towards a role of epidermal AChR in suprabasal processes, most likely terminal differentiation and barrier formation as has been shown in other systems. Most importantly, mast cells are targets of paracrine and endocrine effects mediated by ACh and choline thus modulating inflammatory processes like guttate psoriasis and explaining the clinical efficacity of anticholinergic drugs like atropine. [source] Inhibition of SERCA Ca2+ pumps by 2-aminoethoxydiphenyl borate (2-APB)FEBS JOURNAL, Issue 15 20022-APB reduces both Ca2+ binding, by interfering with the pathway leading to the Ca2+ -binding sites, phosphoryl transfer from ATP 2-Aminoethoxydiphenyl Borate (2-APB) has been extensively used recently as a membrane permeable modulator of inositol-1,4,5-trisphosphate-sensitive Ca2+ channels and store-operated Ca2+ entry. Here, we report that 2-APB is also an inhibitor of sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA) Ca2+ pumps, and additionally increases ion leakage across the phospholipid bilayer. Therefore, we advise caution in the interpretation of results when used in Ca2+ signalling experiments. The inhibition of 2-APB onthe SERCA Ca2+ pumps is isoform-dependent, with SERCA 2B being more sensitive than SERCA 1A (IC50 values for inhibition being 325 and 725 µm, respectively, measured at pH 7.2). The Ca2+ -ATPase is also more potently inhibited at lower pH (IC50 = 70 µm for SERCA1A at pH 6). 2-APB decreases the affinity for Ca2+ binding to the ATPase by more than 20-fold, and also inhibits phosphoryl transfer from ATP (by 35%), without inhibiting nucleotide binding. Activity studies performed using mutant Ca2+ -ATPases show that Tyr837 is critical for the inhibition of activity by 2-APB. Molecular modeling studies of 2-APB binding to the Ca2+ ATPase identified two potential binding sites close to this residue, near or between transmembrane helices M3, M4, M5 and M7. The binding of 2-APB to these sites could influence the movement of the loop between M6 and M7 (L6-7), and reduce access of Ca2+ to their binding sites. [source] Does corporate governance transparency affect the accuracy of analyst forecasts?ACCOUNTING & FINANCE, Issue 5 2006Gauri Bhat M4; O1 Abstract Using country-level proxies for corporate governance transparency, this paper investigates how differences in transparency across 21 countries affect the average forecast accuracy of analysts for the country's firms. The association between financial transparency and analyst forecast accuracy has been well documented in previous published literature; however, the association between governance transparency and analyst forecast accuracy remains unexplored. Using the two distinct country-level factors isolated by Bushman et al. (2004), governance transparency and financial transparency, we investigate whether corporate governance information impacts on the accuracy of earnings forecasts over and above financial information. We document that governance transparency is positively associated with analyst forecast accuracy after controlling for financial transparency and other variables. Furthermore, our results suggest that governance-related disclosure plays a bigger role in improving the information environment when financial disclosures are less transparent. Our empirical evidence also suggests that the significance of governance transparency on analyst forecast accuracy is higher when legal enforcement is weak. [source] Microplane constitutive model for porous isotropic rocksINTERNATIONAL JOURNAL FOR NUMERICAL AND ANALYTICAL METHODS IN GEOMECHANICS, Issue 1 2003k P. Ba Abstract The paper deals with constitutive modelling of contiguous rock located between rock joints. A fully explicit kinematically constrained microplane-type constitutive model for hardening and softening non-linear triaxial behaviour of isotropic porous rock is developed. The microplane framework, in which the constitutive relation is expressed in terms of stress and strain vectors rather than tensors, makes it possible to model various microstructural physical mechanisms associated with oriented internal surfaces, such as cracking, slip, friction and splitting of a particular orientation. Formulation of the constitutive relation is facilitated by the fact that it is decoupled from the tensorial invariance restrictions, which are satisfied automatically. In its basic features, the present model is similar to the recently developed microplane model M4 for concrete, but there are significant improvements and modifications. They include a realistic simulation of (1) the effects of pore collapse on the volume changes during triaxial loading and on the reduction of frictional strength, (2) recovery of frictional strength during shearing, and (3) the shear-enhanced compaction in triaxial tests, manifested by a deviation from the hydrostatic stress,strain curve. The model is calibrated by optimal fitting of extensive triaxial test data for Salem limestone, and good fits are demonstrated. Although these data do not cover the entire range of behaviour, credence in broad capabilities of the model is lend by its similarity to model M4 for concrete,an artificial rock. The model is intended for large explicit finite-element programs. Copyright © 2002 John Wiley & Sons, Ltd. [source] Peroxidase activity, chlorophylls and antioxidant profile of two leaf vegetables (Solanum nigrum L. and Amaranthus cruentus L.) under six pretreatment methods before cookingINTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 1 2008Odunayo Clement Adebooye Summary The study evaluated the effects of six pretreatment methods before cooking on the peroxidase activity, chlorophyll and antioxidant profile of Amaranthus cruentus L. and Solanum nigrum L. The six pretreatments methods used were chopped only (raw sample) (coded M1); chopped and dried at 50 °C for 5 h (coded M2); chopped and squeezed in water (at room temperature) (coded M3); chopped and soaked in warm water (approximately 60 °C), then cooled and squeezed (coded M4); chopped and soaked in salt-treated water (approximately 20 g NaCl per litre of water) for 15 min, then squeezed (coded M5) and chopped and soaked in boiling water (100 °C), then cooled and squeezed (coded M6). The main effect of vegetable type and the main effect of pretreatment methods have significant effects (P 0.05) on the parameters measured, while the interaction of vegetable type and pretreatment methods have no significant effect on the parameters measured. Statistical analyses (P 0.05) showed that chlorophyll a and b occur in ratio 3:1 in the two vegetables, irrespective of the pretreatment imposed. Peroxidase activity test showed that A. cruentus, irrespective of the pretreatment imposed showed, no peroxidase activity, while S. nigrum showed high peroxidase activity for all the pretreatments except for M6. Results showed that there was a significantly (P 0.05) higher content of carotenoids in A. cruentus when compared with S. nigrum, while the total phenolics, total flavonoids and total tannins contents were higher in S. nigrum when compared with A. cruentus, irrespective of the pretreatment method used. For the two vegetables, the percentage losses in total carotenoids, phenolics, flavonoids and total tannins at M6 when compared with M1 were 53.3,60.5%, 55.6,57.1%, 62.4,63.6% and 66.1,73.5%, respectively. There was a sharp drop in the carotenoids, phenolics, flavonoids and tannins contents of the two vegetables at M4 and M6, with both treatments having closely similar values for each parameter. [source] Productivity and Sustainability of Cotton (Gossypium hirsutum L.),Wheat (Triticum aestivum L.) Cropping System as Influenced by Prilled Urea, Farmyard Manure and AzotobacterJOURNAL OF AGRONOMY AND CROP SCIENCE, Issue 5 2004A. Das Abstract Field experiments were conducted at Indian Agricultural Research Institute, New Delhi, during 2001,2002 and 2002,2003, to study the effect of inorganic, organic and Azotobacter combined sources of N on cotton (Gossypium hirsutum L.) and their residual effect on succeeding wheat (Triticum aestivum L.) crop. The results indicated considerable increase in yield attributes and mean seed cotton yield (2.33 Mg ha,1) with the combined application of 30 kg N and farmyard manure (FYM) at 12 Mg ha,1 along with Azotobacter (M4). The treatment in cotton that included FYM, especially when fertilizer N was also applied could either improve or maintain the soil fertility status in terms of available N, P and K. Distinct increase in yield attributes and grain yield of wheat was observed with the residual effect of integrated application of 30 kg N ha,1 + FYM at 12 Mg ha,1 + Azotobacter. Direct application of 120 kg N ha,1 resulted 67.4 and 17.7 % increase in mean grain yield of wheat over no N and 60 kg N ha,1, respectively. Integrated application of organic and inorganic fertilizer is therefore, recommended for higher productivity and sustainability of the cotton,wheat system. [source] Expression of glutathione transferase isoenzymes in the human H295R adrenal cell line and the effect of forskolinJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2002Tuula Stark Abstract In previous studies in our laboratory (L. Mankowitz, L. Staffas, M. Bakke, and J. Lund, Biochem J, 1995, 305, 111,118; L. Staffas, L. Mankowitz, M. Söderström, A. Blanck, I. Porsch-Hällström, C. Sundberg, B. Mannervik, B. Olin, J. Rydström, and J.W. DePierre, Biochem J, 1992, 286, 65,72) isoenzymes of GST, primarily of the , class, have been shown to be downregulated by adrenocorticotropic hormone (ACTH) in rat and mouse adrenal cells. In the present investigation the human adrenal H295R cell line (W.E. Rainey, I.M. Bird, and J.I. Mason, Mol Cell Endocrinol, 1994, 100, 45,50) was examined in a similar manner. Analysis by reverse-phase HPLC revealed that these cells express four isoenzymes of GST, i.e., A1, A2, P1, and M4, as well as another unidentified protein that was retained by our affinity column (elution time of 32 min) and, thus, presumably binds glutathione. Among these forms, A1 was present at the highest level. Upon addition of forskolin (an activator of adenylate cyclase which has been shown previously to mimic the effect of ACTH on adrenal cells) to the culture medium, the level of A1 decreased approximately 70% by forskolin, whereas the levels of the other isoenzymes were slightly increased, and that of the unknown form doubled. Thus, the influence of ACTH on expression of GST isoenzymes in this human adrenal cell line differs from that in rat and mouse adrenal cells. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:169,173, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10034 [source] Characterization of metabolites of tanshinone IIA in rats by liquid chromatography/tandem mass spectrometryJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 5 2006Peng Li Abstract The metabolism of tanshinone IIA was studied in rats after a single-dose intravenous administration. In the present study, 12 metabolites of tanshinone IIA were identified in rat bile, urine and feces with two LC gradients using LC-MS/MS. Seven phase I metabolites and five phase II metabolites of tanshinone IIA were characterized and their molecular structures proposed on the basis of the characteristics of their precursor ions, product ions and chromatographic retention time. The seven phase I metabolites were formed, through two main metabolic routes, which were hydroxylation and dehydrogenation metabolism. M1, M4, M5 and M6 were supposedly tanshinone IIB, hydroxytanshinone IIA, przewaquinone A and dehydrotanshinone IIA, respectively, by comparing their HPLC retention times and mass spectral patterns with those of the standard compounds. The five phase II metabolites identified in this research were all glucuronide conjugates, all of which showed a neutral loss of 176 Da. M9 and M12 were more abundant than other identified metabolites in the bile, which was the main excretion path of tanshinone IIA and the metabolites. M12 was the main metabolite of tanshinone IIA. M9 and M12 were proposed to be the glucuronide conjugates of two different semiquinones and these semiquinones were the hydrogenation products of dehydrotanshinone IIA and tanshinone IIA, respectively. This hydrogenized reaction may be catalyzed by the NAD(P)H: quinone acceptor oxidoreductase (NQO). The biotransformation pathways of tanshinone IIA were proposed on the basis of this research. Copyright © 2006 John Wiley & Sons, Ltd. [source] A counter-clockwise P,T path for the Voltri Massif eclogites (Ligurian Alps, Italy)JOURNAL OF METAMORPHIC GEOLOGY, Issue 7 2005G. VIGNAROLI Abstract Integrated petrological and structural investigations of eclogites from the eclogite zone of the Voltri Massif (Ligurian Alps) have been used to reconstruct a complete Alpine P,T deformation path from burial by subduction to subsequent exhumation. The early metamorphic evolution of the eclogites has been unravelled by correlating garnet zonation trends with the chemical variations in inclusions found in the different garnet domains. Garnet in massive eclogites displays typical growth zoning, whereas garnet in foliated eclogites shows rim-ward resorption, likely related to re-equilibration during retrogressive evolution. Garnet inclusions are distinctly different from core to rim, consisting primarily of Ca-, Na/Ca-amphibole, epidote, paragonite and talc in garnet cores and of clinopyroxene ± talc in the outer garnet domains. Quantitative thermobarometry on the inclusion assemblages in the garnet cores defines an initial greenschist-to-amphibolite facies metamorphic stage (M1 stage) at c. 450,500 °C and 5,8 kbar. Coexistence of omphacite + talc + katophorite inclusion assemblage in the outer garnet domains indicate c. 550 °C and 20 kbar, conditions which were considered as minimum P,T estimates for the M2 eclogitic stage. The early phase of retrograde reactions is polyphase and equilibrated under epidote,blueschist facies (M3 stage), characterized by the development of composite reaction textures (garnet necklaces and fluid-assisted Na-amphibole-bearing symplectites) produced at the expense of the primary M2 garnet-clinopyroxene assemblage. The blueschist retrogression is contemporaneous with the development of a penetrative deformation (D3) that resulted in a non-coaxial fabric, with dominant top-to-the-N sense of shear during rock exhumation. All of that is overprinted by a texturally late amphibolite/greenschist facies assemblages (M4 & M5 stages), which are not associated with a penetrative structural fabric. The combined P,T deformation data are consistent with an overall counter-clockwise path, from the greenschist/amphibolite, through the eclogite, the blueschist to the greenschist facies. These new results provide insights into the dynamic evolution of the Tertiary oceanic subduction processes leading to the building up of the Alpine orogen and the mechanisms involved in the exhumation of its high-pressure roots. [source] High-pressure granulites in the Sanggan area, North China craton: metamorphic evolution, P,T paths and geotectonic significanceJOURNAL OF METAMORPHIC GEOLOGY, Issue 8 2002J. H. Guo Abstract High-pressure basic granulites are widely distributed as enclaves and sheet-like blocks in the Huaian TTG gneiss terrane in the Sanggan area of the Central Zone of the North China craton. Four stages of the metamorphic history have been recognised in mineral assemblages based on inclusion, exsolution and reaction textures integrated with garnet zonation patterns as revealed by compositional maps and compositional profiles. The P,T conditions for each metamorphic stage were obtained using thermodynamically and experimentally calibrated geothermobarometers. The low-Ca core of growth-zoned garnet, along with inclusion minerals, defines a prograde assemblage (M1) of garnet + clinopyroxene + plagioclase + quartz, yielding 700 °C and 10 kbar. The peak of metamorphism at about 750,870 °C and 11,14.5 kbar (M2) is defined by high-Ca domains in garnet interiors and inclusion minerals of clinopyroxene, plagioclase and quartz. Kelyphites or coronas of orthopyroxene + plagioclase ± magnetite around garnet porphyroblasts indicate garnet breakdown reactions (M3) at conditions around 770,830 °C and 8.5,10.5 kbar. Garnet exsolution lamellae in clinopyroxene and kelyphites of amphibole + plagioclase around garnet formed during the cooling process at about 500,650 °C and 5.5,8 kbar (M4). These results help define a sequential P,T path containing prograde, near-isothermal decompression (ITD) and near-isobaric cooling (IBC) stages. The clockwise hybrid ITD and IBC P,T paths of the HP granulites in the Sanggan area imply a model of thickening followed by extension in a collisional environment. Furthermore, the relatively high-pressures (6,14.5 kbar) of the four metamorphic stages and the geometry of the P,T paths suggest that the HP granulites, together with their host Huaian TTG gneisses, represent the lower plate in a crust thickened during collision. The corresponding upper-plate might be the tectonically overlying Khondalite series, which was subjected to medium- to low-pressure (MP/LP: 7,4 kbar) granulite facies metamorphism with a clockwise P,T path including an ITD segment. Both the HP and the MP/LP granulite facies events occurred contemporaneously at c. 1.90,1.85 Ga in a collisional environment created by the assembly process of the North China craton. [source] Role of M2, M3, and M4 muscarinic receptor subtypes in the spinal cholinergic control of nociception revealed using siRNA in ratsJOURNAL OF NEUROCHEMISTRY, Issue 4 2009You-Qing Cai Abstract Muscarinic acetylcholine receptors (mAChRs) are involved in the control of nociception in the spinal cord. The M2, M3, and M4 mAChR subtypes are present in the spinal dorsal horn. However, the role of the individual subtypes in the anti-nociceptive effect produced by mAChR agonists is uncertain. Here, we determined the contribution of M2, M3, and M4 subtypes to spinal muscarinic analgesia by using small-interference RNA (siRNA) targeting specific mAChR subtypes in rats. The neuronal uptake and distribution of a chitosan-siRNA conjugated fluorescent dye in the spinal cord and dorsal root ganglion were confirmed after intrathecal injection. The control and gene-specific siRNA-chitosan complexes were injected intrathecally for three consecutive days. Quantitative reverse-transcription polymerase chain reaction analysis showed that treatment with siRNA targeting M2, M3, or M4 subtype produced a large reduction in the corresponding mRNA levels in the dorsal root ganglion and dorsal spinal cord. Also, the protein levels of the mAChR subtypes in the spinal cord were significantly down-regulated by siRNA treatment, as determined by the immunoprecipitation and receptor-binding assay. Treatment with the M2 -siRNA caused a large reduction in the inhibitory effect of muscarine on the nociceptive withdrawal threshold. Furthermore, M4 knockdown at the spinal level significantly reduced the anti-nociceptive effect of muscarine. However, the anti-nociceptive effect of muscarine was not significantly changed by the M3 -specific siRNA. Our study suggests that chitosan nanoparticles can be used for efficient delivery of siRNA into the neuronal tissues in vivo. Our findings also provide important functional evidence that M2 and M4, but not M3, contribute to nociceptive regulation by mAChRs at the spinal level. [source] Decreased density of muscarinic receptors in the superior temporal gyrusin schizophreniaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2005Chao Deng Abstract Recent studies have indicated that muscarinic receptors are involved in the pathophysiology in schizophrenia, particularly in cognitive deficits. The superior temporal gyrus (STG) is an area that has also been strongly implicated in the pathophysiology of schizophrenia. Therefore, in this study, we investigated the binding density of two muscarinic antagonists, [3H]pirenzepine and [3H]AF-DX384, in the STG of schizophrenia patients compared with controls. A significant decrease (44% in the superficial layers and 48% in the deep layers, P < 0.01) in binding density of [3H]pirenzepine was observed in schizophrenia patients, which suggested a reduction of muscarinic M1 and M4 receptor densities in the STG of schizophrenia patients. A tendency toward decreased [3H]AF-DX384 binding density (34%, P = 0.09) was also observed in schizophrenia patients compared with controls. Because of the positive correlation between [3H]pirenzepine and [3H]AF-DX384 binding, and, insofar as both ligands have high affinities for the M4 receptor, the involvement of M4 receptor alteration is also suggested in the STG in schizophrenia. These results suggest that changes of the muscarinic receptors M1 and M4 might contribute to the STG pathology in schizophrenia. © 2005 Wiley-Liss, Inc. [source] Metabolism and disposition of resveratrol in the isolated perfused rat liver: Role of Mrp2 in the biliary excretion of glucuronidesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2008Alexandra Maier-Salamon Abstract In this study, the hepatic metabolism and transport system for resveratrol was examined in isolated perfused livers from Wistar and Mrp2-deficient TR, rats. Based on extensive metabolism to six glucuronides and sulfates (M1,M6), the hepatic extraction ratio and clearance of resveratrol was very high in Wistar and TR, rats (E: 0.998 vs. 0.999; Cl: 34.9 mL/min vs. 36.0 mL/min). However, biliary excretion and efflux of conjugates differs greatly in TR, rats. While cumulative biliary excretion of the glucuronides M1, M2, M3, and M5 dropped dramatically to 0,6%, their efflux into perfusate increased by 3.6-, 1.8-, 2.5-, and 1.5-fold. In contrast, biliary secretion of the sulfates M4 and M6 was partially maintained in the Mrp2-deficient rats (61% and 39%) with a concomitant decline of their efflux into perfusate by 33.2% and 78.1%. This indicates that Mrp2 exclusively mediates the biliary excretion of resveratrol glucuronides but only partly that of sulfates. Cumulative secretion of unconjugated resveratrol into bile of TR, rats was only reduced by 40%, and into perfusate by 19%, suggesting only a minor role of Mrp2 in resveratrol elimination. In summary, resveratrol was dose-dependently metabolized to several conjugates whereby the canalicular transporter Mrp2 selectively mediated the biliary excretion of glucuronides. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1615,1628, 2008 [source] Disposition and pharmacokinetics of L-N6-(1-iminoethyl)lysine-5-tetrazole-amide, a selective iNOS inhibitor, in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2004Ji Y. Zhang Abstract The metabolism, pharmacokinetics, tissue distribution, and excretion of L-N6-(1-iminoethyl)lysine-5-tetrazole-amide (L-NIL-TA), a selective inducible NO synthase (iNOS) inhibitor, were investigated in rats. [14C]L-NIL-TA is extensively metabolized after either oral or IV administration with a minor amount (<1%) excreted as the prodrug. L-NIL-TA is metabolized via a single hydrolysis pathway to form the active drug, L-N6-(1-iminoethyl)lysine (L-NIL). The oxidative deamination of 2-amino group of L-NIL forms a 2-keto metabolite (M5), which further loses carbon dioxide to yield a carboxylic acid metabolite (M6). Acetylation of L-NIL and M5 resulted in the formations of metabolites M7 and M4, respectively. Complete recovery of the radioactive dose was achieved after either oral (91.2% in urine and 4.66% in feces) and IV (99.3% in urine and 5.11% in feces) administration. L-NIL-TA-related material was extensively distributed to the tissues, with the highest concentration of radioactivity being found in muscle. Maximal concentration of radioactivity was reached between 0.5 and 1 h post-dose in the majority of tissues, with the exception of muscle and skin where the maximal concentrations were achieved at 8 h post-dose. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1229,1240, 2004 [source] Genetic and Pathogenic Variation Among Tobacco Black Shank Strains of Phytophthora parasitica var. nicotianae from the Main Tobacco Growing in ChinaJOURNAL OF PHYTOPATHOLOGY, Issue 5 2003X. G. Zhang Abstract Pathogenic and genetic variability among seven populations of Phytophthora parasitica var. nicotianae from individual tobacco fields (Yunnan, Shandong, Henan, Heilongjiang, Shanxi, Fujian and Sichuan provinces) were investigated using pathogenicity and randomly amplified polymorphic DNA (RAPD) analyses; 63 strains were isolated from different fields of seven tobacco growing regions, using tobacco cv. Hongda as a baiting host. Pathogenic variability was evaluated in greenhouse studies using five tobacco cultivars that have different levels of resistance to tobacco black shank; 75 and 73% of the strains were pathogenic on M3 and M4, 29 and 33% on M1 and M2, and 94% were pathogenic on M5, respectively. Disease severity incited by different strains varied significantly on individual tobacco cultivars. The percentage of strains pathogenic on different cultivars varied among locations. Genotypic variation among 63 strains was evaluated by RAPD analysis. Ten primers detected 89 polymorphic bands. Cluster and principal coordinates analysed cluster groups. the minor group contained 26 strains, and major group contained 37 strains. Estimates of genetic diversity based on RAPD analysis ranged from 0.24 to 0.34 within populations to 0.36 among all strains from all populations. Phytophthora parasitica var. nicotianae populations were genotypically and phenotypically variable, but no distinct genotypic differences were identified among populations from the seven locations. [source] Optical and electrochemical properties of copoly(aryl ether)s consisting of alternate 2,5-distyrylbenzene and electron-transporting oxadiazole or triazole derivativesJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 21 2005Shinn-Horng Chen Abstract New copoly(aryl ether) P1 consisting of alternate electron-transporting 2-(3-(trifluoromethyl)phenyl)-5-(4-(5-(3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)-2,5-bis(hexyloxy)phenyl)-1,3,4-oxadiazole and hole-transporting 2,5-distyrylbenzene (DSB) was synthesized via nucleophilic substitution polymerization. We investigated the optical and electrochemical properties of alternate copoly(aryl ether)s P1,P6, which contain the same hole-transporting DSB segments, but with different electron transporting segments. The effect of trifluoromethyl groups in electron transporting segments is also discussed. Referencing to the spectra of their model compounds M1,M4, the emissions of P1,P3 are dominated exclusively by the hole-transporting fluorophores with longer emissive wavelength about 452,453 nm via efficient excitation energy transfer. Furthermore, P1,P3 also exhibit unique variations in energy transfer in acidic media and solvatochromism in organic solvents. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels of P1,P4, estimated from electrochemical data, are ,5.12, ,5.15, ,5.18, ,5.00 eV and ,2.93, ,3.39, ,3.49, ,2.76 eV, respectively. The electron and hole affinity of P1,P6 can be enhanced simultaneously by introducing isolated hole- and electron-transporting segments in backbone. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5083,5096, 2005 [source] RELATIONSHIP BETWEEN SENSORY AND TEXTURE MEASUREMENT OF JAMUN AND POSITIONING OF JAMUN SAMPLESJOURNAL OF SENSORY STUDIES, Issue 1 2002R. RAVI ABSTRACT Profilograms based on the quantitative descriptive analysis (QDA) of jamun using nine attributes were drawn for four market samples and ten samples prepared using various instant mixes available in the local market. The instrumental texture measurement of shear values were determined for all the samples. Correlations between sensory and instrumental texture measurement (shear force) were studied. The shear values were found to be correlated positively with softness, juiciness and milkiness. Further canonical discriminant analysis was run to position the samples in relation to others. The results indicated that samples M1, M2, M4, S3, S4, S6 and S10 group together in the same quadrant which represents desirable attributes of jamun viz, color, softness, juiciness, milkiness and overall quality. The jamuns from the instant mixes (S) can replace the control samples, traditionally prepared market samples (M) as they match the product profile very closely. [source] Analysis of 4-methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenyl-propyl ester hydrochloride and its major metabolites in rat plasma and tissues by LC-MS/MSJOURNAL OF SEPARATION SCIENCE, JSS, Issue 13 2007Xiaomei Jiang Abstract 4-Methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester hydrochloride (TM-208) is a newly synthesized compound, which has shown excellent in vivo and in vitro anticancer activity and low toxicity. To investigate the metabolism of TM-208 in rats, in the present study, we administered TM-208 orally to rats and analyzed its metabolites existing in rat plasma and central tissues by LC-MS/MS. Rat plasma and tissue samples were collected before or after a single oral dose (250 mg/kg) of TM-208, then the analytes were extracted from samples by liquid,liquid extraction and analyzed using LC-MS/MS. The structures of proposed metabolites were elucidated according to the rules of drug metabolism and disposition in vivo and the characteristic fragmentation behaviors of TM-208 in ESI-ITMSn. Five metabolites (M1,M5) were tentatively or assuredly identified: (2-amino-ethyl)-dithiocarbamic acid 3-cyano-3,3-diphenyl-propyl ester (M1), (2-methylamino-ethyl)-dithiocarbamic acid 3-cyano-3,3-diphenyl-propyl ester (M2), 4-methyl-piperazine-1-carbothioic acid S -(3-cyano-3,3-diphenyl-propyl) ester (M3), piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester (M4), and sulfine of (4-methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester) (M5). [source] Dexmedetomidine or medetomidine premedication before propofol,desflurane anaesthesia in dogsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2006R. J. GÓMEZ-VILLAMANDOS The objective of this study was to evaluate dexmedetomidine as a premedicant in dogs prior to propofol,desflurane anaesthesia, and to compare it with medetomidine. Six healthy dogs were anaesthetized. Each dog received intravenously (i.v.) five preanaesthetic protocols: D1 (dexmedetomidine, 1 ,g/kg, i.v.), D2 (dexmedetomidine, 2 ,g/kg, i.v.), M1 (medetomidine, 1 ,g/kg, i.v.), M2 (medetomidine, 2 ,g/kg, i.v.), or M4 (medetomidine, 4 ,g/kg, i.v.). Anaesthesia was induced with propofol (2.3,3.3 mg/kg) and maintained with desflurane. The following variables were studied: heart rate (HR), mean arterial pressure, systolic arterial pressure, diastolic arterial pressure, respiratory rate (RR), arterial oxygen saturation, end-tidal CO2, end-tidal concentration of desflurane (EtDES) required for maintenance of anaesthesia and tidal volume. Arterial blood pH (pHa) and arterial blood gas tensions (PaO2, PaCO2) were measured during anaesthesia. Time to extubation, time to sternal recumbency and time to standing were also recorded. HR and RR decreased significantly during sedation in all protocols. Cardiorespiratory variables during anaesthesia were statistically similar for all protocols. EtDES was significantly different between D1 (8.1%) and D2 (7.5%), and between all doses of medetomidine. Desflurane requirements were similar for D1 and M2, and for D2 and M4 protocols. No statistical differences were observed in recovery times. The combination of dexmedetomidine, propofol and desflurane appears to be effective for induction and maintenance of general anaesthesia in healthy dogs. [source] ECHA J0843.3,7905: Discovery of an ,old' classical T Tauri star in the , Chamaeleontis clusterMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 2 2002Warrick A. Lawson A limited-area survey of the , Chamaeleontis cluster has identified two new late-type members. The more significant of these is ECHA (=IRAS , a slowly rotating M2 classical T Tauri (CTT) star with a spectrum dominated by Balmer emission. At a distance of 97 pc and cluster age of ,9 Myr, the star is a nearby rare example of an ,old' CTT star and promises to be a rewarding laboratory for the study of disc structure and evolution in pre-main sequence (PMS) stars. The other new member is the M4 weak-lined T Tauri (WTT) star ECHA , which is the lowest mass primary known in the cluster. [source] Detection of muscarinic receptor subtypes in human urinary bladder mucosa: Age and gender-dependent modifications,,§NEUROUROLOGY AND URODYNAMICS, Issue 5 2008Nicola Arrighi Abstract Aims Muscarinic receptor subtypes expressed in the human urinary bladder mucosa were characterized, investigating whether there were gender-dependent differences and if aging could induce changes in their expression. Methods The study was carried out on 34 subjects, 22 men and 12 women, divided in four groups, based on gender and age. Gene expression was evaluated by quantitative RT-PCR. The Western blot was performed using the 4,12% NuPAGE Bis,Tris Gel System. Results The molecular expression of each subtype of the M1 receptor family was observed and it was not influenced either by gender or age. M2 receptor family transcripts revealed that both M2 and M4 were detected and that the M2 transcripts were modified by both gender and age. Indeed, M2 mRNA was lower in old rather than adult men (P,<,0.05), but higher in rather old than adult women (P,<,0.05). Further, adult men expressed more M2 mRNA than adult women (P,<,0.05), while the opposite was detected in old age (P,<,0.05). The Western blot followed by quantification confirmed that the mRNAs were translated into proteins, and that the M2 subtype showed similar modifications found at molecular level. Discussion The selective modification of M2 receptors observed at the urinary bladder mucosa levels indicates that this anatomical structure could play an active role in the pathophysiology of micturition and supports evidence suggesting an effect of antimuscarinic drugs at this level. Whether these results may influence the age-dependent development of micturition disorders remains to be determined. Neurourol. Urodynam. 27:421,428, 2008. © 2007 Wiley-Liss, Inc. [source] Chromosome 8p11.2 translocations: Prevalence, FISH analysis for FGFR1 and MYST3, and clinicopathologic correlates in a consecutive cohort of 13 cases from a single institution,AMERICAN JOURNAL OF HEMATOLOGY, Issue 4 2010Mrinal M. Patnaik Chromosome 8p11.2 translocations result in diverse oncogenic fusion genes involving FGFR1 or MYST3. Among 24,262 unique patient cytogenetic studies performed at the Mayo Clinic, 8p11.2 translocations were identified in 14 cases (,0.06%). FISH analysis was performed in 13 patients (12 had myeloid neoplasms) and revealed abnormalities of MYST3 (n = 4) or FGFR1 (n = 4) in eight patients. MYST3 abnormalities were associated with acute myeloid leukemia (AML), M4 in three and M6 in one. Three of the four FGFR1 -rearranged cases were associated with myeloproliferative neoplasms but none, including the two with sole 8p11.2, displayed the typical phenotype for stem cell leukemia/lymphoma (SCLL) and only one had eosinophilia; the fourth case had AML-M4. FISH did not reveal FGFR1 involvement in the one patient with SCLL. We conclude that neither the SCLL phenotype nor blood eosinophilia is a consistent feature of FGFR1 -associated 8p11.2 translocations; conversely, FISH might not always reveal FGFR1 involvement in typical SCLL. Am. J. Hematol. 2010. © 2010 Wiley-Liss, Inc. [source] Control of Aspergillus growth and aflatoxin production using natural maize phytochemicals under different conditions of water activityPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 8 2006Andrea V Nesci Abstract The effects of the natural phytochemicals trans -cinnamic acid (CA) and ferulic acid (FA) alone at concentrations of 1,25 mM and in 16 combinations (M: mixtures) on growth and aflatoxin B1 production by Aspergillus flavus Link and A. parasiticus Speare were evaluated. Studies on growth rate and aflatoxin B1 production were carried out in vitro in relation to a water activity aw of 0.999, 0.971, 0.955 and 0.937. Overall, CA at concentrations of 10 and 20 mM and FA,CA mixtures M3 (20 + 5 mM respectively), M8 (25 + 5 mM), M9 (1 + 10 mM), M10 (10 + 10 mM), M11 (20 + 10 mM), M12 (25 + 10 mM), M13 (1 + 20 mM), M14 (10 + 20 mM), M15 (20 + 20 mM) and M16 (25 + 20 mM) were the treatments most effective at inhibiting growth of the four species assayed. All strains were much more sensitive to all natural phytochemicals tested on growth rate at aw = 0.937. CA and the FA,CA mixtures M1 (1 + 1 mM respectively), M4 (25 + 1 mM), M5 (1 + 5 mM), M6 (10 + 1 mM), M7 (20 + 1 mM), M8 (25 + 5 mM), M9 (1 + 10 mM), M10 (10 + 10 mM), M11 (20 + 10 mM), M12 (25 + 10 mM), M13 (1 + 20 mM), M14 (10 + 20 mM), M15 (20 + 20 mM) and M16 (25 + 20 mM) completely inhibited aflatoxin B1 production by all strains at aw = 0.999, 0.971, 0.955 and 0.937. Decreased aflatoxin B1 levels in comparison with the control were observed with FA at 1, 10, 20 and 25 mM with the strains RCM89, RCM108 and RCM38 at aw = 0.971, 0.955 and 0.999 respectively. The data show that CA and FA can be considered as effective fungitoxicants for A. flavus and A. parasiticus in in vitro assay. The information obtained is part of an ongoing study to determine their application at the storage level. Copyright © 2006 Society of Chemical Industry [source] Expression of MAC-1 (CD11b) in acute myeloid leukemia (AML) is associated with an unfavorable prognosisAMERICAN JOURNAL OF HEMATOLOGY, Issue 4 2006Michaela Graf Abstract There is evidence to suggest, that cellular adhesion molecules and receptors could play a role in leukemia, e.g., through altered adhesive qualities of leukemic blasts. We have studied the expression of the ,2 -integrin Mac-1 (CD11b) on mononuclear cells in 48 patients with AML at first diagnosis by flow cytometry using a direct fluorescein-conjugated antibody. A case was defined as positive if more than 20% of the cells expressed Mac-1. Within the FAB types, we observed a high expression rate in cases with M5 (100% MAC-1+ cases, 73% MAC-1+ cells), M4 (75% MAC-1+ cases, 48% MAC-1+ cells) and in cases with FAB-M1 with 71% MAC-1+ cases and 29% MAC-1+ cells. Separating our patients' cohort in cytogenetic risk groups, we could detect significant higher proportions of MAC-1+, cases (88% vs. 27%, P = 0.005) and cells (51% vs. 16%, P = 0.015) with poor cytogenetic risk compared to the favorable risk group. For clinical evaluations only patients treated according to the protocols of the German AML Cooperative Group (AML-CG) were included (n = 29, cases with AML-M3 were excluded). More MAC-1+ cases and cells were found in the "non-responders" group (n = 8) compared to the "responders" group (n = 24). We can conclude that AML cases with high MAC-1 expression are characterized by a worse prognosis. Evaluation of MAC-1 expression in AML might therefore contribute clinically important data with respect to develop new therapies that influence the interactions between integrins like MAC-1 on leukemic cells and endothelial or immunoreactive cells. Am. J. Hematol. 81:227,235, 2006. © 2006 Wiley-Liss, Inc. [source] Dual targeting of Myxococcus xanthus protoporphyrinogen oxidase into chloroplasts and mitochondria and high level oxyfluorfen resistancePLANT CELL & ENVIRONMENT, Issue 11 2004S. JUNG ABSTRACT Much attention has been paid to the signal sequences of eukaryotic protoporphyrinogen oxidases (protoxes); both the organelles targeted by protoxes and the role of protoxes in conferring resistance against protox-inhibiting herbicides, such as oxyfluorfen, have been examined. However, there have been no reports on the translocation of prokaryotic protoxes. This study investigated the targeting ability of Myxococcus xanthus protox in vitro and in vivo. In an in vitro translocation assay using a dual import system, M. xanthus protein was detected in chloroplasts and mitochondria, suggesting that the M. xanthus protox protein was targeted into both organelles. In order to confirm the in vitro dual targeting ability of M. xanthus, we used a stable transgenic strategy to investigate dual targeting in vivo. In transgenic rice plants overexpressing M. xanthus protox, M. xanthus protox antibody cross-reacted with proteins with predicted molecular masses of 50 kDa from both chloroplasts and mitochondria, and this in vivo transgene expression corresponded to a prominent increase in chloroplastic and mitochondrial protox activity. Seeds from the transgenic lines M4 and M7 germinated in solid Murashige and Skoog media of up to 500 µm of oxyfluorfen, whereas wild-type seeds did not germinate in 1 µm. After 4-week-old-rice plants were treated with oxyfluorfen for 3 d, lines M4 and M7 exhibited normal growth, whereas the wild-type line was severely bleached and necrotized. The herbicidal resistance is attributed to the insignificant accumulation of photodynamic protoporphyrin IX in cytosol because the high chloroplastic and mitochondrial protox activity in oxyfluorfen-treated transgenic lines, compared with that in oxyfluorfen-treated and untreated wild-type plants, metabolizes protoporphyrinogen IX to chlorophyll and heme. A practical application of the dual targeting of M. xanthus protox for obtaining outstanding resistance to peroxidizing herbicides is discussed. [source] Metabolite identification of a new antitumor agent icotinib in rats using liquid chromatography/tandem mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 14 2008Zhongmin Guan Icotinib, 4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline, is a new antitumor agent. The metabolic pathway of icotinib in rats was studied using liquid chromatography/tandem mass spectrometry (LC/MSn) analysis. Full scan and selected ion monitoring modes were used to profile the possible metabolites of icotinib in rat urine, feces and bile samples. Four phase I metabolites (M1,M4) and two phase II metabolites (M5, M6) were detected and characterized. Multiple-stage mass spectrometry and nuclear magnetic resonance (NMR) spectrometry were employed to elucidate structures of metabolites. Icotinib was metabolized to open the crown ether ring to form the main phase I metabolites. During metabolism, a reactive metabolite was formed. Using semicarbazide as a trapping agent, an intermediate arising from opening of the crown ether ring was detected as an aldehyde product by LC/MS/MS. These data indicated that ring opening of the crown ether was triggered by hydroxylation at the 8,-position of the ring to form a hemiacetal intermediate, which was further oxidized or reduced. Finally, the metabolic pathway of icotinib in rats was proposed. Copyright © 2008 John Wiley & Sons, Ltd. 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