bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and Anticonvulsant Properties of New Mannich Bases Derived from 3‐Aryl‐pyrrolidine‐2,5‐diones. Part 1
Authors: Obniska Jolanta , Kopytko Maciej , Zagórska Agnieszka , Chlebek Iwona , Kamiński Krzysztof
Published: April 2010

A series of new Mannich bases ofN‐[(4‐arylpiperazin‐1‐yl)‐methyl]‐3‐(chlorophenyl)‐pyrrolidine‐2,5‐diones10–23have been synthesized and evaluated for their anticonvulsant activity in maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Their neurotoxicity was determined using a rotorod screen. Several molecules showed a promising anticonvulsant profile especially in the MES‐test. In this model of seizures, the most active wereN‐[{4‐(4‐chlorophenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(3‐chlorophenyl)‐pyrrolidine‐2,5‐dione16andN‐[{4‐(3‐trifluoromethylphenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(3‐chlorophenyl)‐pyrrolidine‐2,5‐dione17with ED50values of 21.4 mg/kg and 28.83 mg/kg, respectively. Selected derivatives10,14, and16were tested in the psychomotor seizure 6‐Hz test from whichN‐[{4‐(2‐chlorophenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(2‐chlorophenyl)‐pyrrolidine‐2,5‐dione10revealed the highest protection with an ED50of 78 mg/kg. Compounds10,12, and17were also tested in the pilocarpine‐induced status PIPS test. Furthermore,17was examined in the hippocampal kindling screen afteri. p.administration to rats.
Amino Acid Derivatives, Part 4: Synthesis and Anti‐HIV Activity of New Naphthalene Derivatives
Authors: Hamad Nawar S. , Al‐Haidery Nahed H. , Al‐Masoudi Iman A. , Sabri Mey , Sabri Luma , Al‐Masoudi Najim A.
Published: April 2010

A new series of 2‐(naphthalen‐2‐yloxy)‐N‐[(aryl‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐triazol‐3‐yl)methyl] acetamides 5a–f was synthesized from naphthalene‐derived glycine derivative 2 via the hydrazinoacetamide analogs 4a–f. Alternatively, treatment of 4a with H2SO4 afforded 2‐(naphthalen‐2‐yloxy)‐N‐((5‐(phenylamino)‐1,3,4‐thiadiazol‐2‐yl)methyl) acetamide 6a. Alkylation or sulphonylation of 5a afforded the S‐alkylated derivatives 7 and 8, respectively. Interestingly, treatment of 3 with methoxide ion gave the triazine derivative 9. The synthesized compounds have been screened for their inhibitory activity against HIV‐1 and HIV‐2 in MT‐4 cells. However, 7 was found to be the potent inhibitor in vitro for the replication of HIV‐1 (EC50 = 0.20 μg/mL), suggesting a new lead in the development of an antiviral agent.
Interplay of transporters and enzymes in the Caco‐2 cell monolayer: I. effect of altered apical secretion
Authors: Fan Jianghong , Maeng Han‐Joo , Pang K. Sandy
Published: April 2010

Interactions are expected between transporters and enzymes that compete for the substrate within the cell, and controversy exists for data interpretation on the interplay between transporters and enzymes. In the Caco‐2 cell monolayer, the increase in mean residence time (MRT) of drug accompanying increased secretion has been construed as the reason for increased metabolism, whereas others hold an opposite view that increased secretion would evoke decreased metabolism in this closed system. A catenary Caco‐2 cell model was used to simulate the effects of altered secretion on metabolism, estimated as the fraction of dose metabolized (fmet) or the extraction ratio (ER). The simulations showed that bothfmetandERvaried inversely with the transporter‐mediated intrinsic clearance for apical secretion (CLint,sec) under linear conditions. Under non‐linear conditions of saturable metabolism, apical absorption, basolateral influx or efflux, the simulatedfmetconsistently bore a reciprocal relationship withCLint,sec. For saturable apical absorption or basolateral efflux, a reciprocal relationship between theERandCLint,secwas also found. However, under conditions of saturable metabolism or basolateral influx, the pattern of change in theERbecame dependent on the administration sites, showing increasing patterns for apical dosing but decreasing patterns for basolateral dosing with increasing values ofCLint,sec. In general,fmetconsistently demonstrated an inverse relationship withCLint,sec, whereasER, failing to include the drug in the donor side, would not show the same pattern of change in metabolism especially for apical dosing, since a substantial amount of drug was back‐secreted into the apical compartment. Copyright © 2010 John Wiley & Sons, Ltd.
Contributions of human cytochrome P450 enzymes to glyburide metabolism
Authors: Zhou Lin , Naraharisetti Suresh B. , Liu Li , Wang Honggang , Lin Yvonne S. , Isoherranen Nina , Unadkat Jashvant D. , Hebert Mary F. , Mao Qingcheng
Published: April 2010

Glyburide (GLB) is a widely used oral sulfonylurea for the treatment of gestational diabetes. The therapeutic use of GLB is often complicated by a substantial inter‐individual variability in the pharmacokinetics and pharmacodynamics of the drug in human populations, which might be caused by inter‐individual variations in factors such as GLB metabolism. Therefore, there has been a continued interest in identifying human cytochrome P450 (CYP) isoforms that play a major role in the metabolism of GLB. However, contrasting data are available in the present literature in this regard. The present study systematically investigated the contributions of various human CYP isoforms (CYP3A4, CYP3A5, CYP2C8, CYP2C9 and CYP2C19) toin vitrometabolism of GLB. GLB depletion and metabolite formation in human liver microsomes were most significantly inhibited by the CYP3A inhibitor ketoconazole compared with the inhibitors of other CYP isoforms. Furthermore, multiple correlation analysis between GLB depletion and individual CYP activities was performed, demonstrating a significant correlation between GLB depletion and the CYP3A probe activity in 16 individual human liver microsomal preparations, but not between GLB depletion and the CYP2C19, CYP2C8 or CYP2C9 probe activity. By using recombinant supersomes overexpressing individual human CYP isoforms, it was found that GLB could be depleted by all the enzymes tested; however, the intrinsic clearance (Vmax/Km) of CYP3A4 for GLB depletion was 4–17 times greater than that of other CYP isoforms. These results confirm that human CYP3A4 is the major enzyme involved in thein vitrometabolism of GLB. Copyright © 2010 John Wiley & Sons, Ltd.
Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited
Authors: Wang Weirong , Prueksaritanont Thomayant
Published: April 2010

In this report, the utility of a commonly used interspecies scaling method to predict the systemic clearance (CL) of therapeutic proteins in humans was evaluated. Based on analysis of a pharmacokinetic data set of 34 therapeutic proteins, including 12 monoclonal antibodies (mAbs) and Fc fusion proteins, humanCLcan generally be predicted reasonably well with simple allometric scaling and a fixed exponent of 0.8:∼95% of the cases predicted values within 2‐fold of the observed values when usingCLdata from multiple species, or∼90% simply usingCLfrom monkeys. Specific to mAbs/Fc fusion proteins, scaling from monkeyCLusing a fixed exponent of 0.8 gave an excellent prediction; all predictedCLvalues were within 2‐fold of the corresponding observed values. Compared with the simple allometric scaling method that uses a fitted exponent fromCLdata of ≥3 preclinical species, the fixed exponent approach with 1–2 preclinical species is simple, resource‐saving and minimizes systematic bias. Together with its overall satisfactory prediction accuracy, especially in the absence of non‐linear pharmacokinetics and species‐specific clearance mechanisms, this fixed exponent method affords a viable alternative to other published allometric methods, including the Rule of Exponents (ROE). Copyright © 2010 John Wiley & Sons, Ltd.
Micronuclei in the blood and bone marrow cells of mice exposed to specific complex time‐varying pulsed magnetic fields
Authors: Reddy Siddharth B. , Weller Julie , Desjardins‐Holmes Dawn , Winters Tara , Keenliside Lynn , Prato Frank S. , Prihoda Thomas J. , Vijayalaxmi  , Thomas Alex W.
Published: April 2010

For 8 weeks, adult CD‐1 male mice were continuously exposed to complex time‐varying pulsed magnetic fields (PMF) generated in the horizontal direction by a set of square Helmholtz coils. The PMF were <1000 Hz and delivered at a peak flux density of 1 mT. Sham‐exposed mice were kept in a similar exposure system without a PMF. Positive control animals exposed to 1 Gy gamma radiation were also included in the study. Blood samples were collected before (time 0) and at 2, 4, 6, and 8 weeks. All mice were euthanized at the end of 8 weeks and their bone marrow was collected. From each blood and bone marrow sample, smears were prepared on microscope slides, fixed in absolute methanol, air‐dried, and stained with acridine orange. All slides were coded and examined using a fluorescence microscope. The extent of genotoxicity and cytotoxicity was assessed from the incidence of micronuclei (MN) and percent polychromatic erythrocytes (PCE) in the blood and bone marrow, respectively. The data indicated that both indices in PMF‐exposed mice were not significantly different from those observed in sham‐exposed animals. In contrast, positive control mice exhibited significantly increased MN, and decreased percentages of PCE in both tissues. Thus, the overall data suggested that 8 weeks of continuous exposure to PMF did not induce significantly increased genotoxicity and cytotoxicity in experimental mice. Further investigations are underway using other genotoxicity assays (comet assay, γ‐H2AX foci, and chromosomal aberrations) to assess genotoxicity following PMF exposure. Bioelectromagnetics 31:445–453, 2010. © 2010 Wiley‐Liss, Inc.
Process optimization of the integrated synthesis and secretion of ectoine and hydroxyectoine under hyper/hypo‐osmotic stress
Authors: Fallet C. , Rohe P. , Franco‐Lara E.
Published: April 2010

The synthesis and secretion of the industrial relevant compatible solutes ectoine and hydroxyectoine using the halophile bacterium Chromohalobacter salexigens were studied and optimized. For this purpose, a cascade of two continuously operated bioreactors was used. In the first bioreactor, cells were grown under constant hyperosmotic conditions and thermal stress driving the cells to accumulate large amounts of ectoines. To enhance the overall productivity, high cell densities up to 61 g L−1 were achieved using a cross‐flow ultrafiltration connected to the first bioreactor. In the coupled second bioreactor the concentrated cell broth was subjected to an osmotic and thermal down‐shock by addition of fresh distilled water. Under these conditions, the cells are forced to secrete the accumulated intracellular ectoines into the medium to avoid bursting. The cultivation conditions in the first bioreactor were optimized with respect to growth temperature and medium salinity to reach the highest synthesis (productivity); the second bioreactor was optimized using a multi‐objective approach to attain maximal ectoine secretion with simultaneous minimization of cell death and product dilution caused by the osmotic and thermal down‐shock. Depending on the cultivation conditions, intracellular ectoine and hydroxyectoine contents up to 540 and 400 mg per g cell dry weight, respectively, were attained. With a maximum specific growth rate of 0.3 h−1 in defined medium, productivities of approximately 2.1 g L−1 h−1 secreted ectoines in continuous operation were reached. Biotechnol. Bioeng. 2010;107: 124–133. © 2010 Wiley Periodicals, Inc.
Highly efficient deletion of FUT8 in CHO cell lines using zinc‐finger nucleases yields cells that produce completely nonfucosylated antibodies
Authors: Malphettes Laetitia , Freyvert Yevgeniy , Chang Jennifer , Liu Pei‐Qi , Chan Edmond , Miller Jeffrey C. , Zhou Zhe , Nguyen Thu , Tsai Christina , Snowden Andrew W. , Collingwood Trevor N. , Gregory Philip D. , Cost Gregory J.
Published: April 2010

IgG1 antibodies produced in Chinese hamster ovary (CHO) cells are heavily α1,6‐fucosylated, a modification that reduces antibody‐dependent cellular cytotoxicity (ADCC) and can inhibit therapeutic antibody function in vivo. Addition of fucose is catalyzed by Fut8, a α1,6‐fucosyltransferase. FUT8−/− CHO cell lines produce completely nonfucosylated antibodies, but the difficulty of recapitulating the knockout in protein‐production cell lines has prevented the widespread adoption of FUT8−/− cells as hosts for antibody production. We have created zinc‐finger nucleases (ZFNs) that cleave the FUT8 gene in a region encoding the catalytic core of the enzyme, allowing the functional disruption of FUT8 in any CHO cell line. These reagents produce FUT8−/− CHO cells in 3 weeks at a frequency of 5% in the absence of any selection. Alternately, populations of ZFN‐treated cells can be directly selected to give FUT8−/− cell pools in as few as 3 days. To demonstrate the utility of this method in bioprocess, FUT8 was disrupted in a CHO cell line used for stable protein production. ZFN‐derived FUT8−/− cell lines were as transfectable as wild‐type, had similar or better growth profiles, and produced equivalent amounts of antibody during transient transfection. Antibodies made in these lines completely lacked core fucosylation but had an otherwise normal glycosylation pattern. Cell lines stably expressing a model antibody were made from wild‐type and ZFN‐generated FUT8−/− cells. Clones from both lines had equivalent titer, specific productivity distributions, and integrated viable cell counts. Antibody titer in the best ZFN‐generated FUT8−/− cell lines was fourfold higher than in the best‐producing clones of FUT8−/− cells made by standard homologous recombination in a different CHO subtype. These data demonstrate the straightforward, ZFN‐mediated transfer of the Fut8− phenotype to a production CHO cell line without adverse phenotypic effects. This process will speed the production of highly active, completely nonfucosylated therapeutic antibodies. Biotechnol. Bioeng. 2010;106: 774–783. © 2010 Wiley Periodicals, Inc.
Production of cell culture (MDCK) derived live attenuated influenza vaccine (LAIV) in a fully disposable platform process
Authors: George Meena , Farooq Masiha , Dang Thi , Cortes Bernadette , Liu Jonathan , Maranga Luis
Published: April 2010

The majority of influenza vaccines are manufactured using embryonated hens' eggs. The potential occurrence of a pandemic outbreak of avian influenza might reduce or even eliminate the supply of eggs, leaving the human population at risk. Also, the egg‐based production technology is intrinsically cumbersome and not easily scalable to provide a rapid worldwide supply of vaccine. In this communication, the production of a cell culture (Madin‐Darby canine kidney (MDCK)) derived live attenuated influenza vaccine (LAIV) in a fully disposable platform process using a novel Single Use Bioreactor (SUB) is presented. The cell culture and virus infection was maintained in a disposable stirred tank reactor with PID control of pH, DO, agitation, and temperature, similar to traditional glass or stainless steel bioreactors. The application of this technology was tested using MDCK cells grown on microcarriers in proprietary serum free medium and infection with 2006/2007 seasonal LAIV strains at 25–30 L scale. The MDCK cell growth was optimal at the agitation rate of 100 rpm. Optimization of this parameter allowed the cells to grow at a rate similar to that achieved in the conventional 3 L glass stirred tank bioreactors. Influenza vaccine virus strains, A/New Caledonia/20/99 (H1N1 strain), A/Wisconsin/67/05 (H3N2 strain), and B/Malaysia/2506/04 (B strain) were all successfully produced in SUB with peak virus titers ≥8.6 log10 FFU/mL. This result demonstrated that more than 1 million doses of vaccine can be produced through one single run of a small bioreactor at the scale of 30 L and thus provided an alternative to the current vaccine production platform with fast turn‐around and low upfront facility investment, features that are particularly useful for emerging and developing countries and clinical trial material production. Biotechnol. Bioeng. 2010;106: 906–917. © 2010 Wiley Periodicals, Inc.
Support Effects in the Gold‐Catalyzed Preferential Oxidation of CO
Authors: Ivanova Svetlana , Pitchon Véronique , Petit Corinne , Caps Valérie
Published: April 2010

The study of support effects on the gold‐catalyzed preferential oxidation of carbon monoxide in the presence of hydrogen (PROX reaction) is possible only with careful control of the gold particle size, which is facilitated by the application of the direct anionic exchange method. Catalytic evaluation of thermally stable gold nanoparticles, with an average size of around 3 nm on a variety of supports (alumina, titania, zirconia, or ceria), clearly shows that the influence of the support on the CO oxidation rate is of primary importance under CO+O2 conditions and that this influence becomes secondary in the presence of hydrogen. The impact of the support surface structure on the oxidation rates, catalyst selectivity, and catalyst activation/deactivation is investigated in terms of oxygen vacancies, oxygen mobility, OH groups, and surface area on the oxidation rates, catalyst selectivity and catalyst activation/deactivation. It allows the identification of key morphological and structural features of the support to ensure high activity and selectivity in the gold‐catalyzed PROX reaction.
Artificial Metalloenzymes
Authors: Rosati Fiora , Roelfes Gerard
Published: April 2010

Artificial metalloenzymes have emerged as a promising approach to merge the attractive properties of homogeneous catalysis and biocatalysis. The activity and selectivity, including enantioselectivity, of natural metalloenzymes are due to the second coordination sphere interactions provided by the protein. Artificial metalloenzymes aim at harnessing second coordination sphere interactions to create transition metal complexes that display enzyme‐like activities and selectivities. In this Review, the various approaches that can be followed for the design and optimization of an artificial metalloenzyme are discussed. An overview of the synthetic transformations that have been achieved using artificial metalloenzymes is provided, with a particular focus on recent developments. Finally, the role that the second coordination sphere plays in artificial metalloenzymes and their potential for synthetic applications are evaluated.
Novel tolerance interval model for the estimation of the shelf life of pharmaceutical products
Authors: Komka Kinga , Kemény Sándor , Bánfai Balázs
Published: April 2010

The main objective of the stability study of pharmaceutical products is to estimate the shelf life indicated on the container label. For the determination of the label shelf life the International Conference on Harmonisation (ICH) Guideline recommends the confidence interval approach, but its adequacy is questionable. Instead of the current regulation, several proposals are known in the literature applying the tolerance interval approach. The aim of our paper is to extend the tolerance interval model assuming two distinct influence sources, namely the tablet‐to‐tablet variability and the analytical measurement error. Another main concept in the paper is that the tolerance interval is constructed for the true (and not for the measured) assay content. Investigating the influence of several factors on the width of the tolerance interval, a simulation is performed applying different number of samples and repeated analysis, as well as different variance components regarding the tablet‐to‐tablet variability and the analytical measurement error. An example is also given to illustrate the difference between the former and the proposed tolerance interval models and to compare them with the present regulation of the ICH. Copyright © 2010 John Wiley & Sons, Ltd.
Principles of Proper Validation: use and abuse of re‐sampling for validation
Authors: Esbensen Kim H. , Geladi Paul
Published: April 2010

Validation in chemometrics is presented using theexemplarcontext of multivariate calibration/prediction. A phenomenological analysis of common validation practices in data analysis and chemometrics leads to formulation of a set of generic Principles of Proper Validation (PPV), which is based on a set of characterizing distinctions: (i) Validation cannot be understood by focusing on the methods of validation only; validation must be based on full knowledge of the underlying definitions, objectives, methods, effects and consequences—which are all outlined and discussed here. (ii) Analysis of proper validation objectives implies that there is one valid paradigm only: test set validation. (iii) Contrary to much contemporary chemometric practices (and validationmyths), cross‐validation is shown to be unjustified in the form of monolithic application of a one‐for‐all procedure (segmented cross‐validation) on all data sets. Within its own design and scope, cross‐validation is in reality a sub‐optimalsimulationof test set validation, crippled by a critical sampling variance omission, as it manifestly is based on one data set only (training data set). Other re‐sampling validation methods are shown to suffer from the same deficiencies. The PPV are universal and can be applied to all situations in which the assessment of performance is desired: prediction‐, classification‐, time series forecasting‐, modeling validation. The key element of PPV is the Theory of Sampling (TOS), which allow insight into all variance generating factors, especially the so‐called incorrect sampling errors, which, if not properly eliminated, are responsible for a fatal inconstant sampling bias, for which no statistical correction is possible. In the light of TOS it is shown how a second data set (test set, validation set) is critically necessary for the inclusion of the sampling errors incurred in all ‘future’ situations in which the validated model must perform. Logically, therefore, all one data set re‐sampling approaches for validation, especially cross‐validation and leverage‐corrected validation, should be terminated, or at the very least used only with full scientific understanding and disclosure of their detrimental variance omissions and consequences. Regarding PLS‐regression, an emphatic call is made for stringent commitment to test set validation based on graphical inspection of pertinentt–uplots for optimal understanding of theX–Yinterrelationships and for validation guidance. QSAR/QSAP forms a partial exemption from the present test set imperative with no generalization potential. Copyright © 2010 John Wiley & Sons, Ltd.
RuII Multinuclear Metallosupramolecular Rack‐Type Architectures of Polytopic Hydrazone‐Based Ligands: Synthesis, Structural Features, Absorption Spectra, Redox Behavior, and Near‐Infrared Luminescence
Authors: Stadler Adrian‐Mihail , Puntoriero Fausto , Nastasi Francesco , Campagna Sebastiano , Lehn Jean‐Marie
Published: April 2010

A novel class of polytopic hydrazone‐based ligands was synthesized. They gave heteroleptic RuII polynuclear rack‐like complexes of formula [Runterpyn(bridging molecular strand)]2n+ (terpy=2,2′:6′,2′′‐terpyridine). The new rack‐like systems can be viewed as being made of two identical or roughly identical peripheral subunits separated by several similar metal‐containing spacer subunits. The presence of pyrazine or pyrimidine units within the molecular multitopic strands introduces additional chemical diversity: whereas a pyrimidine unit leads to appended orthogonal subunits that are on the same side with regard to the main molecular strand, a pyrazine unit leads to orthogonal subunits that lie on different sides. Mixing pyrazine and pyrimidine units within the same (bridging) molecular strand also allows peculiar and topographically controlled geometries to be obtained. Redox studies provided evidence that each species undergoes reversible redox processes at mild potentials, which can be assigned to specific subunits of the multicomponent arrays. Non‐negligible electronic coupling takes place among the various subunits, and some electron delocalization extending over the overall bridging molecular strand takes place. In particular, oxidation data suggest that the systems can behave as p‐type “molecular wires” and reduction data indicate that n‐type electron conduction can occur within the multimetallic framework. All the multinuclear racks exhibit 3MLCT emission, both at 77 K in rigid matrix and at 298 K in fluid solution, which takes place in the near‐infrared region (emission maxima in the 1000–1100 nm region), and is quite structured. Rigidity of the molecular structures and delocalization within the large bridging ligands are proposed to contribute to the occurrence of the rather uncommon MLCT infrared emission, which is potentially interesting for optical communication devices.
A Flexible Approach to Azasugars: Asymmetric Total Syntheses of (+)‐Castanospermine, (+)‐7‐Deoxy‐6‐epi‐castanospermine, and (+)‐1‐epi‐Castanospermine
Authors: Liu Gang , Wu Tian‐Jun , Ruan Yuan‐Ping , Huang Pei‐Qiang
Published: April 2010

The asymmetric total synthesis of natural azasugars (+)‐castanospermine, (+)‐7‐deoxy‐6‐epi‐castanospermine, and synthetic (+)‐1‐epi‐castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)‐8. The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama‐type reaction with either chiral or achiral aldehydes (≥95 % de; de=diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereoselectivities. The method also provides a flexible access to structural arrays of 5‐(α‐hydroxyalkyl)tetramic acids, such as 17/34, and 5‐(α‐hydroxyalkyl)‐4‐hydroxyl‐2‐pyrrolidinones, such as 18 and 25/35 a. The method constitutes the first realization of the challenging chiral synthons A and D and thus of the conceptually attractive retrosynthetic analysis shown in Scheme 1 in a highly enantioselective manner.
Steric and Electronic Influence on Photochromic Switching of N,C‐Chelate Four‐Coordinate Organoboron Compounds
Authors: Amarne Hazem , Baik Chul , Murphy Stephen K. , Wang Suning
Published: April 2010

A four‐coordinate organoboron compound B(ppy)Mes2 (1, ppy=2‐phenylpyridyl, Mes=mesityl) was previously found to undergo reversible photochromic switching through the formation/breaking of a CC bond, accompanied by a dramatic color change from colorless to dark blue. To understand this unusual phenomenon, a series of new four‐coordinate boron compounds based on the ppy‐chelate ligand and its derivatives have been synthesized. In addition, new N,C‐chelate ligands based on benzo[b]thiophenylpyridine and indolylpyridine have also been synthesized and their boron compounds were investigated. The crystal structures of most of the new compounds were determined by X‐ray diffraction analysis. UV/Vis, NMR, and electrochemical methods were used to monitor the photoisomerization process. DFT calculations were performed for all compounds to understand the photophysical and electronic properties of this class of molecules. The results of our study showed that the bulky mesityl group is necessary for photochromic switching. Electron‐donating and electron‐withdrawing groups on the ppy chelate have a distinct impact on the photoisomerization rate and the photochemical stability of the molecule. Furthermore, we have found that the non‐ppy‐based N,C‐chelate ligands such as benzo[b]thiophenepyridyl can also promote photoisomerization of the boron chromophore in the same manner as the ppy chelate, but the product is thermally unstable.
Construction of 2,3‐Dihydrofuran Cores through the [3+2] Cycloaddition of Gold α‐Carbonylcarbenoids with Alkenes
Authors: Li Chia‐Wen , Lin Guan‐You , Liu Rai‐Shung
Published: April 2010

Treatment of 2‐epoxy‐1‐alkynylbenzenes with electron‐rich alkenes and a [AuCl(PR3)]/AgX catalyst in CH2Cl2 led to the formation of 2‐alkenyl‐1‐(2,3‐dihydrofuran‐4‐yl)benzenes. This transformation comprises of a gold‐catalyzed redox reaction to form a gold α‐carbonylcarbenoid initially, which then reacts in situ with an alkene in a [3+2] cycloaddition. A range of alkenes are amenable to this tandem reaction, amongst them α‐substituted styrenes, enol ethers, and 2,3‐dimethylbutadienes. Deuterium‐labeling experiments suggest a stepwise mechanism for the α‐carbonylcarbenoid/alkene [3+2] cycloaddition. The resulting 2,3‐dihydrofuran products allow access to diverse oxacyclic compounds through a stereoselective ene–oxonium reaction initiated by treatment with HOTf (1 mol %; Tf=trifluoromethanesulfonyl). A stepwise pathway is proposed for this reaction. The feasibility for direct transformation of 2‐alkenyl‐1‐alkynylbenzenes into the desired 2,3‐dihydrofuran products through initial m‐chloroperbenzoic acid oxidation, followed by the addition of gold catalyst and alkene, has also been demonstrated.
A delay‐dependent robust fuzzy MPC approach for nonlinear CSTR
Authors: Chen Qiu‐Xia , Yu Li
Published: April 2010

Based on Takagi–Sugeno (T–S) fuzzy models, a robust fuzzy model predictive control (MPC) algorithm is presented for a class of nonlinear time‐delay systems with input constraints. Delay‐dependent sufficient conditions for the robust stability of the closed‐loop system are derived, and the condition for the existence of the fuzzy model predictive controller is formulated in terms of nonlinear matrix inequality via the parallel distributed compensation (PDC) approach. By using a novel matrix transform technique, a receding optimization problem with linear matrix inequality (LMIs) constraints is constructed to design the desired controllers with an on‐line optimal receding horizon guaranteed cost. Finally, an example of continuous stirred tank reactors (CSTR) is given to demonstrate the effectiveness of the proposed results.
Bubble shape, gas flow and gas–liquid mass transfer in pulp fibre suspensions
Authors: Ishkintana L. K. , Bennington C. P. J.
Published: April 2010

Gas–liquid mass transfer in pulp fibre suspensions in a batch‐operated bubble column is explained by observations of bubble size and shape made in a 2D column. Two pulp fibre suspensions (hardwood and softwood kraft) were studied over a range of suspension mass concentrations and gas flow rates. For a given gas flow rate, bubble size was found to increase as suspension concentration increased, moving from smaller spherical/elliptical bubbles to larger spherical‐capped/dimpled‐elliptical bubbles. At relatively low mass concentrations (Cm = 2–3% for the softwood and Cm ≅ 7% for the hardwood pulp) distinct bubbles were no longer observed in the suspension. Instead, a network of channels formed through which gas flowed. In the bubble column, the volumetric gas–liquid mass transfer rate, kLa, decreased with increasing suspension concentration. From the 2D studies, this occurred as bubble size and rise velocity increased, which would decrease overall bubble surface area and gas holdup in the column. A minimum in kLa occurred between Cm = 2% and 4% which depended on pulp type and was reached near the mass concentration where the flow channels first formed.
Polycyclic aromatic hydrocarbons (PAHs) adsorption on solid surfaces applied to waste lubricant oils recovery process
Authors: Filho José Lima Assunção , de Moura Lyzette Gonçalves Moraes , Ramos Antonio Carlos da Silva
Published: April 2010

Lubricant oils undergo degradation increasing polycyclic aromatic hydrocarbons (PAHs) concentration. In this work, PAHs adsorption onto activated carbon, powder silica, and powder chitosan surfaces was estimated, with their concentrations in organic solvents (ethanol, 2‐propanol, 1‐butanol, and terc‐butanol) monitored by UV‐visible absorption. Equilibrium concentration was attained after 72 h and the isotherms presented characteristic of multilayer formation. The greater surface density was determined for the chitosan, but the system containing activated carbon and 1‐butanol presented better efficiency for PAHs removal. Results indicated that the adsorption evaluated in this work can be a potential stage in the waste lubricant oils global recovery process.
A simple method for identifying bubbling/jetting regimes transition from large submerged orifices using electrical capacitance tomography (ECT)
Authors: Cai Qingbai , Shen Xuesong , Shen Chunyin , Dai Gance
Published: April 2010

The bubbling–jetting transition regimes from large orifice submerged in water were investigated for various orifice diameters. A simple and fast way for identifying the regime transition was successfully developed using electrical capacitance tomography (ECT). In all the experiments deionised water was liquid phase and air was gas phase. Orifice gas velocity (VN) and orifice diameter (do) were varied from 0.8 to 186 m/s and 4–21 mm, respectively. It was found that the VN,trans. strongly depends on the orifice diameter. In the small orifice diameter (do < 10 mm), VN,trans. greatly decreases with the increase of orifice diameter. However, in the large orifice diameter (do > 10 mm), the effect of orifice diameter on the transition velocity is insignificant. Finally, the data obtained by ECT compares with other works and the dimensionless orifice Reynolds number (Reo ∼11,000) is preferred to identify the bubbling–jetting transition regimes.
Stokes slip flow through a lattice of parallel plates
Authors: Wang C. Y.
Published: April 2010

Low Reynolds number slip flow through periodic parallel slats is studied. The efficient method of domain decomposition and eigenfunction expansion is used. It is found that even small partial slip greatly decreases the resistance of the filter and the entrance (exit) effects.
Inverted‐Takotsubo Pattern Cardiomyopathy Secondary to Pheochromocytoma: A Clinical Case and Literature Review
Authors: Kim Stephen , Yu Anthony , Filippone Lea A. , Kolansky Daniel M. , Raina Amresh
Published: April 2010

Takotsubo cardiomyopathy is an increasingly recognized clinical syndrome of transient left ventricular dysfunction, commonly with apical ballooning, in the context of physical or emotional stress. Recently, an inverted‐Takotsubo contractile pattern has been described with hypokinesis of the basal and mid‐ventricular segments and sparing of the apex. We report a case of a 30‐year‐old man presenting with transient left ventricular dysfunction in an inverted‐Takotsubo contractile pattern, associated with a newly discovered pheochromocytoma, and present a literature review of the inverted‐Takotsubo contractile pattern cardiomyopathy. Copyright © 2010 Wiley Periodicals, Inc.
Should We Measure C‐reactive Protein on Earth or Just on JUPITER?
Authors: Bajpai Ambareesh , Goyal Abhinav , Sperling Laurence
Published: April 2010

Evidence for the role of inflammation in the pathogenesis of atherosclerosis is compelling and has generated interest in high‐sensitivity C‐reactive protein (hs‐CRP) as a marker of cardiovascular risk. Data regarding hs‐CRP and cardiovascular risk, though largely consistent, is of unclear clinical relevance. Most recently, the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial has led to further debate regarding the utility of hs‐CRP. This article provides a comprehensive review of the data regarding cardiovascular risk and hs‐CRP with an emphasis on the JUPITER trial and concludes with an evidence‐based analysis of the current role of hs‐CRP in cardiovascular risk assessment. Copyright © 2010 Wiley Periodicals, Inc.
Cardiovascular Manifestations in Patients With Thrombotic Thrombocytopenic Purpura: A Single‐center Experience
Authors: Gandhi Kaushang , Aronow Wilbert S. , Desai Harit , Amin Harshad , Sharma Mala , Lai Hoang M. , Singh Parminder
Published: April 2010

Background

Cardiovascular manifestation in patients with thrombotic thrombocytopenic purpura.

Hypothesis

The aim of this study was to investigate the incidence of acute myocardial infarction (AMI), arrhythmias, congestive heart failure, and mortality in patients hospitalized for thrombotic thrombocytopenic purpura (TTP).

Methods

Thirty‐eight patients (27 women and 11 men), mean age 44 years, were hospitalized with the diagnosis of TTP confirmed by a hematologist. We investigated the incidence of AMI which developed during hospitalization for TTP. AMI was diagnosed by new electrocardiographic changes, increased serum cardiac troponin I levels, and clinical symptomatology. The patients with AMI were also monitored for development of arrhythmias during hospitalization.

Results

Of the 38 patients, 8 (21%) developed new Q‐wave AMI. There was no significant difference in baseline characteristics between patients who developed AMI and those who did not develop AMI. Of the 8 patients with AMI, 2 (25%) developed atrial fibrillation, 1 (13%) developed atrial flutter, 1 (13%) developed supraventricular tachycardia, and 2 (25%) developed congestive heart failure. Death occurred in 3 of 8 patients (38%) with AMI and in 1 of 30 patients (3%) without AMI (P < 0.01).

Conclusions

New Q‐wave AMI developed in 21% of 38 patients hospitalized with TTP. Supraventricular tachyarrhythmias developed in 50% of 8 patients with TTP who developed AMI. Patients hospitalized for TTP should be monitored for adverse cardiac events due to the high incidence of new AMI, supraventricular tachyarrhythmias, and mortality. Copyright © 2010 Wiley Periodicals, Inc.
Changes in Inflammatory Biomarkers in Patients Treated With Ticagrelor or Clopidogrel
Authors: Husted Steen , Storey Robert F. , Harrington Robert A. , Emanuelsson Håkan , Cannon Christopher P.
Published: April 2010

Background

Inflammation is a key factor in the development of atherosclerotic disease and acute coronary syndromes (ACS). The P2Y12 receptor antagonists ticagrelor (AZD6140) and clopidogrel may have anti‐inflammatory effects. The objective of this analysis from the Dose Confirmation Study Assessing Anti‐Platelet Effects of AZD6140 vs Clopidogrel in NSTEMI 2 (DISPERSE 2) trial was to compare ticagrelor and clopidogrel for effects on the inflammatory biomarkers C‐reactive protein (CRP), interleukin 6 (IL‐6), myeloperoxidase (MPO), and soluble CD40 ligand (sCD40L).

Hypothesis

Ticagrelor inhibits the P2Y12 receptor and inflammation to a greater extent than clopidogrel in nonST‐segment elevation ACS (NSTE‐ACS) patients.

Methods

In a double‐blind, double‐dummy, multicenter trial, 990 patients who had been hospitalized within the previous 48 hours with NSTE‐ACS were randomized to receive ticagrelor 90 mg twice daily, ticagrelor 180 mg twice daily, or clopidogrel 300 mg initially and then 75 mg once daily. Within the ticagrelor groups, patients were also randomized to receive or not receive a loading dose of ticagrelor 270 mg initially. All patients received standard treatment for ACS, which included 325 mg aspirin initially and 75 to 100 mg aspirin each day subsequently. Inflammatory biomarkers were measured at baseline, upon hospital discharge, and after 4 weeks.

Results

Inflammatory biomarker measurements were not significantly different among treatment groups at baseline, discharge, and 4 weeks.

Conclusions

Ticagrelor and clopidogrel appeared not to differ in this study with respect to the inflammatory biomarkers CRP, IL‐6, MPO, and sCD40L in patients with NSTE‐ACS. Copyright © 2010 Wiley Periodicals, Inc.
Long‐term Outcome of Patients Treated With Prophylactic Nesiritide for the Prevention of Acute Kidney Injury Following Cardiovascular Surgery
Authors: Lingegowda Vijaykumar , Van Quoc C. , Shimada Michiko , Beaver Thomas M. , Dass Bhagwan , Sood Puneet , Ahsan Ejaz A.
Published: April 2010

Background

Previously, we reported that the prophylactic use of nesiritide did not reduce the incidence of dialysis or death following cardiovascular (CV) surgery despite reducing the incidence of acute kidney injury (AKI) in the immediate postoperative period. Therefore, we investigated whether the observed renal benefits of nesiritide had any long‐term impact on cumulative patient survival and renal outcomes.

Methods

Participants of the Nesiritide Study, a previously reported prospective, double‐blind, placebo‐controlled, randomized clinical trial investigating the effect of nesiritide on the incidence of dialysis or death at 21 days in adult patients undergoing high‐risk CV surgery, were included in the study. Data of the participants' most recent health and renal function status were obtained using institutional review board‐approved patient questionnaires, medical records, and the database of the Social Security Administration.

Results

Data on all 94 patients from the Nesiritide Study were obtained. The mean follow‐up period was 20.8 ± 10.4 months. No differences in cumulative survival between the groups were noted at follow‐up (nesiritide 77.7% vs placebo 81.6%,P= 0.798). Patients with in‐hospital incidence of AKI had a higher rate of mortality than those with no AKI (AKI 41.4% vs no AKI 10.7%,P= 0.002). However, differences in survival time were not significant between the groups when the analysis was restricted to patients with AKI (nesiritide 16.8 ± 4 months vs placebo 18.5 ± 2.3 months,P= 0.729).

Conclusions

Renoprotection provided by nesiritide in the immediate postoperative period was not associated with improved long‐term survival in patients undergoing high‐risk CV surgery. Copyright © 2010 Wiley Periodicals, Inc.
Coronary Artery Collaterals
Authors: Richard Conti C.
Published: April 2010

After hearing a lecture I gave on chronic stable angina, a friend of mine and fellow cardiologist from Florida, Steven Shang, MD, approached me to discuss the relevance of coronary artery collateral blood flow. Copyright © 2010 Wiley Periodicals, Inc.
Design, Synthesis, and Preliminary Biological Evaluation of Pyrrolo[3,4‐c]quinolin‐1‐one and Oxoisoindoline Derivatives as Aggrecanase Inhibitors
Authors: Cappelli Andrea , Nannicini Chiara , Valenti Salvatore , Giuliani Germano , Anzini Maurizio , Mennuni Laura , Giordani Antonio , Caselli Gianfranco , Stasi Luigi Piero , Makovec Francesco , Giorgi Gianluca , Vomero Salvatore
Published: April 2010

A small set of aggrecanase inhibitors based on the pyrrolo[3,4‐c]quinolin‐1‐one or oxoisoindoline frameworks bearing a 4‐(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS‐5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS‐5 and ADAMTS‐4. Among the compounds containing the pyrrolo[3,4‐c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS‐5 and ADAMTS‐4, with IC50 values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11. Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS‐5 and ‐4. The structure–activity relationship analysis of pyrroloquinolinone derivatives 2 a–i suggests that the carboxylate or hydroxamate groups of compounds 2 a,b play a key role in the interaction of these compounds with ADAMTS‐5 and ‐4. On the other hand, the oxoisoindoline derivatives 3 a,b lack significant ADAMTS‐4 inhibitory activity and inhibit ADAMTS‐5 showing IC25 values in the micromolar range.
von Kries versus color constancy
Authors: van Trigt C.
Published: April 2010

We derive the conditions for which the illuminant‐independent behavior of von Kries quotients is good. They are in qualitative agreement with those obtained in the experiment. The key concepts are as follows: narrow sensitivities, their approximation by a δ‐function at an appropriate wavelength, and the nature of the reflectance and spectral distribution functions for which the δ‐function approximation is good. Color constancy theory aims to construct strictly or almost illuminant‐independent perceptual, achromatic and chromatic variables from illuminant‐dependent tristimulus values. Deficiencies due to ignoring metamerism and, in constructions, the constraints that spectral distribution functions are nonnegative and reflectance functions assume values between 0 and 1, are identified and corrected, if remediable. Variables are constructed with a more favorable illuminant‐independent behavior than von Kries quotients. Helmholtz's (conjectured) interpretation of color constancy is proved to be correct. If color and lightness are illuminant‐independent functions of these variables, equality of appearance under test and reference sources occurs if (and under weak conditions only if) they possess the same values under these sources. The resulting chromatic adaptation transform specifies an earlier open proposal (Color Science. New York: Wiley; 1982. 434 p). We prove a result concerning the role of color in discrimination. © 2010 Wiley Periodicals, Inc. Col Res Appl, 2010
Planar Au/TiO2 Model Catalysts: Fabrication, Characterization and Catalytic Activity
Authors: Eyrich Menhild , Kielbassa Stefan , Diemant Thomas , Biskupek Johannes , Kaiser Ute , Wiedwald Ulf , Ziemann Paul , Bansmann Joachim
Published: April 2010

Different types of planar Au/TiO2 model catalysts are produced on TiO2(110) single‐crystal substrates and thin TiO2 films on Ru(0001) by physical vapor deposition of gold under ultrahigh‐vacuum (UHV) conditions or by micelle‐based chemical routes. Both the Au nanoparticles and the support are characterized by surface‐science‐based methods (such as atomic force microscopy and X‐ray photoelectron spectroscopy) as well as by transmission electron microscopy. Finally, the activity of the model catalysts in the CO oxidation reaction is analyzed in a microflow reactor. Au/TiO2(110) model catalysts with a stoichiometric TiO2(110) support exhibit only a low catalytic activity compared to those with a reduced crystal and Au/TiO2 model catalysts with thin TiO2 films on Ru(0001) as a substrate. The possible influence of Ti interstitials in the reduced TiO2(110) substrates on the CO oxidation activity is discussed.
Unraveling the Pressure Effect on Nucleation Processes of Amyloidogenic Proteins
Authors: Gruzielanek Stefan , Zhai Yong , Winter Roland
Published: April 2010

The influence of pressure on the nucleation rate of insulin under fibril‐forming conditions was studied and subsequently analysed using classical nucleation theory. The aim was a better understanding and quantification of the influence of pressure on protein aggregation/fibrillation reactions. The application of pressure has a drastic accelerating effect on the nucleation and growth process of insulin fibrils. We show that this effect arises from a volume decrease upon nucleus formation, due to formation of a less hydrated and more compact transition state that can be quantified extending nucleation theory by a pressure–volume term. Conversely, the absolute values of the lag time and the critical size of the nucleus cannot be satisfactorily described by the classical nucleation theory, which might be due to the presence of secondary effects, such as parallel aggregation pathways or fragmentation processes.