bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly Diastereoselective Additions to Polyhydroxylated Pyrrolidine Cyclic Imines: Ready Elaboration of Aza‐Sugar Scaffolds To Create Diverse Carbohydrate‐Processing Enzyme Probes
Authors: Chapman Timothy M. , Courtney Steve , Hay Phil , Davis Benjamin G.
Published: July 2003

Representative diastereomeric, erythritol and threitol polyhydroxylated pyrrolidine imine scaffolds have been rapidly elaborated to diversely functionalized aza‐sugars through highly diastereoselective organometallic (RM) additions (R=Me, Et, allyl, hexenyl, Ph, Bn, pMeO‐Bn). The yields for these additions have all been substantially enhanced from previously optimised levels (<58 %) for normal additions using a reverse addition procedure (e.g. R=Ph; 44 % normal mode → 78 % reverse mode). The high diastereoselectivities (>98 % de for all except R=Me) are consistent with additions that are controlled by the configuration of the C‐2 centre adjacent to the azomethine imine carbon and the conformation of the pyrrolidine imine. The high potential of this method was demonstrated by concise syntheses of 1‐epi‐ and 2‐epi‐desacetylanisomycins. In addition, the late stage addition of hydrophobic substituents, which this imine addition methodology allows, enabled the preparation of novel aza‐sugars with enhanced inhibitory potential. This was highlighted by the screening of a representative selection of these “hydrophobically‐modified” aza‐sugars against a diverse panel of 12 non‐mammalian and human carbohydrate‐processing enzymes. This identified a novel nanomolar α‐galactosidase inhibitor (IC50=250 nM) and a novel highly selective glucosylceramide synthase inhibitor (IC50=52 μM, no α‐glucosidase inhibition at 1 mM). Furthermore, analysis of the structure–activity relationships of racemic series of inhibitors allowed some validation of Fleet's mirror‐image enzyme active site postulate.
Combined Effects of Electrostatic and π–π Stacking Interactions: Selective Binding of Nucleotides and Aromatic Carboxylates by Platinum(II)–Aromatic Ligand Complexes
Authors: Yajima Tatsuo , Maccarrone Giuseppe , Takani Masako , Contino Annalinda , Arena Giuseppe , Takamido Reiko , Hanaki Mieko , Funahashi Yasuhiro , Odani Akira , Yamauchi Osamu
Published: July 2003

Adduct formations of PtII complexes containing an aromatic diimine (DA) and an L‐amino acid (A) with an aromatic carboxylate (AR) or a mononucleotide (NMP) has been studied by synthetic, structural, spectroscopic, and calorimetric methods. Several adducts between PtII complexes, [Pt(DA)(L‐A)] (charges are omitted; DA=2,2′‐bipyrimidine (bpm); A=L‐arginine (L‐Arg), L‐alaninate (L‐Ala), and AR (=indole‐3‐acetate (IA), gentisate (GA)) or GMP were isolated as crystals and structurally characterized by the X‐ray diffraction method. GMP in [Pt(bpm)(Arg)](GMP)⋅5 H2O was revealed to be bound through the π–π stacking and guanidinium–phosphate hydrogen bonds. The [Pt(DA)(A)]‐AR and ‐NMP systems in aqueous solution exhibited NMR upfield shifts of the aromatic ring proton signals due to stacking. The stability constants (K) for the adducts were determined by absorption and NMR spectra and calorimetric titrations. The log K values were found to be in the range 1.40–2.29 for AR and 1.8–3.3 for NMP, the order for NMP being GMP>AMP>CMP>UMP. The ΔH ° values were negative for all the systems studied, and the values for AR (=IA and GA) were more negative than those for NMP, indicating that ARs are stronger electron donors than NMPs. Comparison of the log K values for [Pt(bpm)(L‐Arg)] and [Pt(bpm)(L‐Ala)] (Ala=alaninate) indicated that the Arg moiety further stabilized the adducts by the guanidinium–carboxylate or –phosphate hydrogen bonds. The combined effects of weak interactions on the stability of the adducts in solution are discussed on the basis of the thermodynamic parameters and solid state structures.
Amphiphilic Polymer Supports for the Asymmetric Hydrogenation of Amino Acid Precursors in Water
Authors: Zarka M. Tobias , Nuyken Oskar , Weberskirch Ralf
Published: July 2003

This paper describes the synthesis and characterization of a new class of amphiphilic, water‐soluble diblock copolymers based on 2oxazoline derivatives with pendent (2S,4S)‐4‐diphenylphosphino‐2‐(diphenylphosphinomethyl)pyrrolidine (PPM) units in the hydrophobic block. The synthetic strategy involves the preparation of a diblock copolymer precursor with ester functionalities in the side chain; which were converted into carboxylic acids in a polymer‐analogous step and finally reacted with the PPM ligand. The structures of the copolymers were characterized by 1H and 31P NMR spectroscopy and GPC measurements. Subsequently, these polymers were successfully utilized as a polymeric support for the asymmetric hydrogenation of 1) (Z)‐α‐acetamido cinnamic acid and 2) methyl (Z)‐α‐acetamido cinnamate in water, showing 90 % substrate conversion at 25 °C within 20 minutes at atmospheric H2 pressure (1 bar) for methyl (Z)‐α‐acetamido cinnamate.
The Use of Imidazolium Ionic Liquids for the Formation and Stabilization of Ir0 and Rh0 Nanoparticles: Efficient Catalysts for the Hydrogenation of Arenes
Authors: Fonseca Gledison S. , Umpierre Alexandre P. , Fichtner Paulo F. P. , Teixeira Sergio R. , Dupont Jairton
Published: July 2003

Stable transition‐metal nanoparticles of the type [M0]n are easily accessible through the reduction of IrI or RhIII compounds dissolved in “dry” 1‐n‐butyl‐3‐methylimidazolium hexafluorophosphate ionic liquid by molecular hydrogen. The formation of these [M0]n nanoparticles is straightforward; they are prepared in dry ionic liquid whereas the presence of the water causes the partial decomposition of ionic liquid with the formation of phosphates, HF and transition‐metal fluorides. Transmission electron microscopy (TEM) observations and X‐ray diffraction analysis (XRD) show the formation of [Ir0]n and [Rh0]n nanoparticles with 2.0–2.5 nm in diameter. The isolated [M0]n nanoparticles can be redispersed in the ionic liquid, in acetone or used in solventless conditions for the liquid–liquid biphasic, homogeneous or heterogeneous hydrogenation of arenes under mild reaction conditions (75 °C and 4 atm). The recovered iridium nanoparticles can be reused several times without any significant loss in catalytic activity. Unprecedented total turnover numbers (TTO) of 3509 in 32 h, for arene hydrogenation by nanoparticles catalysts, have been achieved in the reduction of benzene by the [Ir0]n in solventless conditions. Contrarily, the recovered Rh0 nanoparticles show significant agglomeration into large particles with a loss of catalytic activity. The hydrogenation of arenes containing functional groups, such as anisole, by the [Ir0]n nanoparticles occurs with concomitant hydrogenolysis of the CO bond, suggesting that these nanoparticles behave as “heterogeneous catalysts” rather than “homogeneous catalysts”.
U‐Pin Polyamide Motif for Recognition of the DNA Minor Groove
Authors: Heckel Alexander , Dervan Peter B.
Published: July 2003

DNA‐binding hairpin pyrrole–imidazole polyamides with γ‐aminobutyric acid as a turn‐forming residue tolerate A⋅T or T⋅A base pairs under the turn. U‐pins—polyamides with a different turn—have been synthesized and their DNA binding properties were studied. The two turn‐forming residues are connected via the ring nitrogens using variable length aliphatic linkers ((CH2)n, n=3–6). Through optimization of the linker length and the substituents at the 2‐position of the pyrrole residue on the U‐turn, polyamides with G⋅C/C⋅G tolerant turns could be found, which bind to DNA in a predictable manner.
New Molecular Topologies by Fourfold Metathesis Reactions within a Hydrogen‐Bonded Calix[4]arene Dimer
Authors: Vysotsky Myroslav O. , Bolte Michael , Thondorf Iris , Böhmer Volker
Published: July 2003

A calix[4]arene tetrapentyl ether in the cone conformation substituted at its wide rim by four m‐(ω‐octenyloxy)phenyl urea groups forms hydrogen‐bonded dimeric capsules in dichloromethane/benzene (95:5). Metathesis reaction with Grubbs' catalyst under high‐dilution conditions (1.1×10−4 M) followed by hydrogenation leads to a covalent connection of all the urea groups within a dimer. Three topologically different products may be expected in such a reaction: a bis[2]catenane, a doubly bridged monocatenane and a tetrabridged capsule. All three possible reaction products could be isolated in an overall yield up to 60 % for the separated and purified compounds. Their identification was based on the NMR patterns which reflect the characteristic symmetry properties of the isomeric products especially in the region of the hydrogen‐bonded NH protons and were further confirmed by MALDI‐TOF mass spectra. Further structural support for the bis[2]catenane comes from a single‐crystal X‐ray structure, although severe disorder prevents the localization of all atoms in the aliphatic chains connecting the two calix[4]arenes. Kinetic studies for the guest release/exchange (cyclohexane against the solvent [D6]benzene) do not show remarkable differences between the starting dimer and the additionally linked dimers, while the mobility of an included tetraethylammonium cation is obviously more restricted.
On the Total Synthesis and Determination of the Absolute Configuration of Rishirilide B: Exploitation of Subtle Effects to Control the Sense of Cycloaddition of o‐Quinodimethides
Authors: Yamamoto Kana , Hentemann Martin F. , Allen John G. , Danishefsky Samuel J.
Published: July 2003

The total synthesis of racemic rishirilide B has been accomplished. The synthesis serves to define the relative relationships of its stereogenic centers. Also, starting with readily available chiral pool, ent‐rishirilide B was synthesized, thereby demonstrating that natural configuration of rishirilide B. The defining step in our total synthesis is the facile cycloreversion of the bis(siloxy)benzocyclobutane and the intermolecular o‐quinodimethide Diels–Alder cycloaddition. We believe that the tight regiochemical guidance in this step arises from a meshing of the electron‐donating effects of the symmetry‐perturbing aromatic OTBS group of the o‐quinodimethide diene with the reactivity differential of the dienophile (enedione), modulated by the hydroxyl group at the α‐position. The validity of the hypothesis of hydroxy‐directed activation of its vicinal ketone function in the context of the enedione dienophile warrants further study. This type of activation may find broader applications in distinguishing reactivity profiles of key closely related functional groups in organic substrates.
Orthopalladated and ‐platinated Bulky Triarylphosphite Complexes: Synthesis, Reactivity and Application as High‐Activity Catalysts for Suzuki and Stille Coupling Reactions
Authors: Bedford Robin B. , Hazelwood (néeWelch) Samantha L. , Limmert Michael E. , Albisson David A. , Draper Sylvia M. , Scully P. Noelle , Coles Simon J. , Hursthouse Michael B.
Published: July 2003

Bulky triarylphosphite ligands undergo facile orthometallation reactions with palladium and platinum precursors. The crystal structure of an example of the resultant palladacycles has been determined. The reactivity of some of the metallacycles with HCl, monodentate and bidentate phosphines and sodium diethyldithiocarbamate has been investigated, and the crystal structure of a diethyldithiocarbamate adduct of a palladacycle is presented. The palladacyclic complexes prove to be extremely active catalysts for the Suzuki coupling of aryl bromides with aryl boronic acids. They can also be used as catalysts for the coupling of alkylboronic acids. Meanwhile di‐ and trialkyl phosphine adducts of one of the palladacycles shows very high activity in the Suzuki coupling of aryl chlorides and can also be used to good effect for the Stille coupling of these substrates. The role of the phosphite ligand in the Suzuki coupling of aryl chlorides seems to be one of increasing catalyst longevity by stabilisation of the Pd0 resting state.
Allenes as Carbon Nucleophiles in Intramolecular Attack on (π‐1,3‐Diene)palladium Complexes: Evidence for trans Carbopalladation of the 1,3‐Diene
Authors: Dorange Ismet , Löfstedt Joakim , Närhi Katja , Franzén Johan , Bäckvall Jan‐E.
Published: July 2003

Reaction of allene‐substituted cyclohexa‐ and cyclohepta‐1,3‐dienes with [PdCl2(PhCN)2] gave η3‐(1,2,3)‐cyclohexenyl‐ and η3‐(1,2,3)‐cycloheptenylpalladium complexes, respectively, in which CC bond formation between the allene and the 1,3‐diene has occurred. Analysis of the (π‐allyl)palladium complexes by NMR spectroscopy, using reporter ligands, shows that the CC bond formation has occurred by a trans carbopalladation involving nucleophilic attack by the middle carbon atom of the allene on a (π‐diene)palladium(II) complex. The stereochemistry of the (π‐allyl)palladium complexes was confirmed by benzoquinone‐induced stereoselective transformations to allylic acetates.
Cover Picture: U‐Pin Polyamide Motif for Recognition of the DNA Minor Groove (Chem. Eur. J. 14/2003)
Authors: Heckel Alexander , Dervan Peter B.
Published: July 2003

The cover picture shows a DNA double helix with a pyrrole/imidazole‐polyamide bound to the minor groove. The hydrogen bond recognition pattern for the edges of the four Watson–Crick base pairs on the floor of the DNA minor groove is represented as a series of dips and bumps which are read by the corresponding bumps and dips on the edges of four ring pairs of the polyamide. These building blocks can also be seen on the table and the illustration in the back shows the selection rules. The DNA‐bound polyamide is a U‐pin with a G/C‐tolerant turn. For details about this new polyamide motif see the report by P. B. Dervan et al. on p. 3353 ff.
Retinal remodeling triggered by photoreceptor degenerations
Authors: Jones Bryan W. , Watt Carl B. , Frederick Jeanne M. , Baehr Wolfgang , Chen Ching‐Kang , Levine Edward M. , Milam Ann H. , Lavail Matthew M. , Marc Robert E.
Published: July 2003

Many photoreceptor degenerations initially affect rods, secondarily leading to cone death. It has long been assumed that the surviving neural retina is largely resistant to this sensory deafferentation. New evidence from fast retinal degenerations reveals that subtle plasticities in neuronal form and connectivity emerge early in disease. By screening mature natural, transgenic, and knockout retinal degeneration models with computational molecular phenotyping, we have found an extended late phase of negative remodeling that radically changes retinal structure. Three major transformations emerge: 1) Müller cell hypertrophy and elaboration of a distal glial seal between retina and the choroid/retinal pigmented epithelium; 2) apparent neuronal migration along glial surfaces to ectopic sites; and 3) rewiring through evolution of complex neurite fascicles, new synaptic foci in the remnant inner nuclear layer, and new connections throughout the retina. Although some neurons die, survivors express molecular signatures characteristic of normal bipolar, amacrine, and ganglion cells. Remodeling in human and rodent retinas is independent of the initial molecular targets of retinal degenerations, including defects in the retinal pigmented epithelium, rhodopsin, or downstream phototransduction elements. Although remodeling may constrain therapeutic intervals for molecular, cellular, or bionic rescue, it suggests that the neural retina may be more plastic than previously believed. J. Comp. Neurol. 464:1–16, 2003. © 2003 Wiley‐Liss, Inc.
Single‐cell study of motor cortex projections to the barrel field in rats
Authors: Veinante Pierre , Deschênes Martin
Published: July 2003

In freely moving rats, whisking is associated with a slow modulation of neuronal excitability in the primary somatosensory cortex. Because it persists after the blockade of vibrissa input, it was suggested that the slow modulation might be mediated by motor–sensory corticocortical connections and perhaps result from the corollary discharges of corticofugal cells. In the present study, we identified motor cortical cells that project to the barrel field and reconstructed their axonal projections after juxtacellularly staining single cells with a biotinylated tracer. On the basis of the final destination of main axons, two groups of neurons contribute to motor–sensory projections: callosal cells (87.5%) and corticofugal cells (12.5%). Axon collaterals of callosal cells arborize in layers five to six of the granular and dysgranular zones and give off several branches that ascend between the barrels to ramify in the molecular layer. In contrast, the axon collaterals of corticofugal cells do not ramify in the infragranular layers but in layer 1. The origin of the majority of motor sensory projections from callosally projecting cells does not support the notion that the slow modulation results from the corollary discharges of corticofugal axons. It would rather originate from a separate population of cells, which could output the slow signal to the barrel field in parallel with the corticofugal commands to a brainstem pattern generator. As free whisking is characterized by bilateral concerted movements of the vibrissae, the transcallosal contribution of motor–sensory axons represents a substrate for synchronizing the slow modulation across both hemispheres. J. Comp. Neurol. 464:98–103, 2003. © 2003 Wiley‐Liss, Inc.
The negative impact of perceiving discrimination on collective well‐being: the mediating role of perceived ingroup status
Authors: Leonardelli Geoffrey J. , Tormala Zakary L.
Published: July 2003

Previous research has found that, among stigmatized group members, perceiving discrimination against the ingroup simultaneously yields a positive indirect effect on self‐worth (mediated by ingroup identification) and a negative direct effect (Branscombe, Schmitt, & Harvey, 1999). This study not only replicated these effects with a sample of women, but also revealed that the negative direct effect was mediated by perceived status of the ingroup: as perceived discrimination increased, perceived ingroup status decreased, which in turn lowered collective self‐worth. Perceiving discrimination also increased the accessibility of the stigmatized group's devalued status. A new direction for future research may be to consider when stigmatized group members might affirm the ingroup rather than protect self‐worth. Copyright © 2003 John Wiley & Sons, Ltd.
Cognitive dissonance, double forced compliance, and commitment
Authors: Joule Robert‐Vincent , Azdia Touati
Published: July 2003

Double forced compliance situations are studied to analyse how attitudes change after the performance of two behaviours, rather than just one as in standard forced (or induced) compliance situations. In the present experiment, subjects were asked to execute two successive counterattitudinal behaviours: writing an essay in favour of selective admission to the third year of university (first behaviour) and giving a convincing speech in favour of selective admission (second behaviour). The first behaviour was always performed in a high‐commitment context (free choice, publicness, and consequences), whereas the second was performed in a high‐commitment context as well as in a low‐commitment context (free choice, anonymity, and no consequences). The following hypotheses were tested. (1) If the second behaviour is performed in a high‐commitment context, it will increase the dissonance induced by the first. (2) If the second behaviour is performed in a low‐commitment context, it will decrease the dissonance induced by the first. The results confirmed both hypotheses, which comply with the radical version of dissonance theory (Beauvois & Joule, 1996, 1999). As a whole, these results are incompatible with competing theories of Festinger's theory of dissonance (1957), and in particular with self‐perception and impression‐management theories. Copyright © 2003 John Wiley & Sons, Ltd.
Non‐linear forecasts of stock returns
Authors: Kanas Angelos
Published: July 2003

Following recent non‐linear extensions of the present‐value model, this paper examines the out‐of‐sample forecast performance of two parametric and two non‐parametric nonlinear models of stock returns. The parametric models include the standard regime switching and the Markov regime switching, whereas the non‐parametric are the nearest‐neighbour and the artificial neural network models. We focused on the US stock market using annual observations spanning the period 1872–1999. Evaluation of forecasts was based on two criteria, namely forecast accuracy and forecast encompassing. In terms of accuracy, the Markov and the artificial neural network models produce at least as accurate forecasts as the other models. In terms of encompassing, the Markov model outperforms all the others. Overall, both criteria suggest that the Markov regime switching model is the most preferable non‐linear empirical extension of the present‐value model for out‐of‐sample stock return forecasting. Copyright © 2003 John Wiley & Sons, Ltd.
Selection of Value‐at‐Risk models
Authors: Sarma Mandira , Thomas Susan , Shah Ajay
Published: July 2003

Value‐at‐Risk (VaR) is widely used as a tool for measuring the market risk of asset portfolios. However, alternative VaR implementations are known to yield fairly different VaR forecasts. Hence, every use of VaR requires choosing among alternative forecasting models. This paper undertakes two case studies in model selection, for the S&P 500 index and India's NSE‐50 index, at the 95% and 99% levels. We employ a two‐stage model selection procedure. In the first stage we test a class of models for statistical accuracy. If multiple models survive rejection with the tests, we perform a second stage filtering of the surviving models using subjective loss functions. This two‐stage model selection procedure does prove to be useful in choosing a VaR model, while only incompletely addressing the problem. These case studies give us some evidence about the strengths and limitations of present knowledge on estimation and testing for VaR. Copyright © 2003 John Wiley & Sons, Ltd.
Transport of glutathione conjugates and chemotherapeutic drugs by RLIP76 (RALBP1): A novel link between G‐protein and tyrosine kinase signaling and drug resistance
Authors: Awasthi Sanjay , Singhal Sharad S. , Sharma Rajendra , Zimniak Piotr , Awasthi Yogesh C.
Published: July 2003

Our studies have shown that RLIP76 (RALBP1), a 76 kDa Ral‐binding, Rho/Rac‐GAP and Ral effector protein, is a novel multispecific transporter of xenobiotics as well as GS‐Es. Like previously characterized ABC transporters, it mediates ATP‐dependent transport of structurally unrelated amphiphilic xenobiotics and displays inherent ATPase activity, which is stimulated by its substrate allocrites. It does not have significant sequence homology with ABC transporters and differs from the ABC transporters in several other important aspects, including (i) lack of any close homologs in humans, (ii) lack of a classical Walker domain, (iii) integral membrane association without clearly defined transmembrane domains and (iv) its role as a direct link to Ras/Ral/Rho and EGF‐R signaling through its multifunctional nature, including GAP activity, regulation of exocytosis as well as clathrin‐coated pit–mediated receptor endocytosis. Its multifunctional nature derives from the presence of multiple motifs, including a Rho/Rac GAP domain, a Ral effector domain binding motif, 2 distinct ATP‐binding domains, a H+‐ATPase domain, PKC and tyrosine kinase phosphorylation sites and the ability to undergo fragmentation into multiple smaller peptides which participate as components of macromolecular functional complexes. One of the physiologic functions of RLIP76 is regulation of intracellular concentration of the electrophilic intermediates of oxidative lipid metabolism by mediating efflux of GS‐E formed from oxidative degradation of arachidonic acid, including leukotrienes and the 4HNE‐GSH conjugate. RLIP76‐mediated transport of amphiphilic chemotherapeutic agents such as anthracyclines and vinca alkaloids as well as GS‐E produced during oxidative metabolism places this multifunctional protein in a central role as a resistance mechanism for preventing apoptosis caused by chemotherapeutic agents and a variety of external/internal stressors, including oxidative stress, heat shock and radiation. © 2003 Wiley‐Liss, Inc.
Acceleration of tumor growth and peri‐tumoral blood clotting by imatinib mesylate (Gleevec™)
Authors: Samoszuk Michael , Corwin Mark A.
Published: July 2003

Imatinib mesylate (Gleevec™) inhibits the BCR‐ABL tyrosine kinase in chronic granulocytic leukemia. Previous studies have demonstrated that imatinib mesylate also inhibits the survival and functions of normal mast cells by interfering with the receptor tyrosine kinase for stem cell factor (SCF), c‐kit, which is expressed by mast cells. Because mast cells extensively surround many types of cancer and contain powerful anticoagulants such as heparin, we investigated the effects of imatinib mesylate on blood clotting and tumor growth within subcutaneous implants of a mammary adenocarcinoma cell line (4T1) in BALB/c mice. After 5 days of oral treatment with 10 mg/kg of the drug, the average mass of the tumors in treated mice (198 ± 42 mg, n = 5) was significantly (p < 0.05) greater than the average mass of the tumors from untreated (control) mice (60 ± 23 mg, n = 5). Moreover, the tumors in the treated mice were frequently surrounded by large lakes of clotted blood that were not evident in tumors from the control mice. Accelerated growth and blood clotting were also observed in tumor‐bearing mice treated with heparinase I enzyme to destroy endogenous mast cell heparin and in NDST‐2 knockout mice in which there is a targeted disruption in the gene coding for mast cell heparin synthesis. We conclude that imatinib mesylate accelerated the growth and peri‐tumoral blood clotting of implants of mammary adenocarcinoma in mice. These results suggest that imatinib mesylate may have significant effects on mast cells infiltrating tumors, in addition to its other biologic activities. Our results also indicate that the mechanism of this effect may be related to the anticoagulant properties of mast cell heparin. © 2003 Wiley‐Liss, Inc.
Stromelysin‐1/matrix metalloproteinase‐3 (MMP‐3) expression accounts for invasive properties of human astrocytoma cell lines
Authors: Mercapide Javier , Lopez De Cicco Ricardo , Castresana Javier S. , Klein‐Szanto Andres J.P.
Published: July 2003

Tumor invasiveness is an intrinsic feature of most glial tumors that accounts for their malignant and locally destructive nature. We evaluated the subcutaneous (sc) tumorigenicity and in vivo invasiveness of 9 astrocytoma cell lines together with their respective metalloprotease activity in order to establish their biologic behavior and malignant potential. Invasiveness was assessed with an in vivo invasion assay using tracheal xenotransplants subcutaneously implanted into Scid mice. This assay permitted us to evaluate the penetration of tumor cells into the transplanted deepithelialized tracheas previously inoculated with either normal primary glial cells or with astrocytoma‐derived cell lines. Although only 2 cell lines were tumorigenic after sc inoculation, 5 out of 9 tumor cell lines were tumorigenic in the tracheal graft system. The astrocytoma cell lines showed varying levels of penetration into the tracheal wall. The tumor lines GOS3, M059K, CCFSTTG1 and A172, as well as primary normal astrocytes, were nontumorigenic and noninvasive in this experimental model. LN405, SW1088 and SW1783 cells that were not tumorigenic as sc xenotransplants, on the other hand, grew well in the tracheal graft system showing low levels of in vivo invasiveness. U87MG and U118MG cells were tumorigenic as sc xenotransplants and showed high levels of invasiveness. In parallel to these in vivo studies, the constitutive levels of secreted gelatinases and stromelysins (MMP‐3 and MMP‐11) were investigated using conditioned media submitted to gelatin or casein‐substrate zymography and Western blot analysis. Neither the gelatinases (MMP‐2 and MMP‐9) nor MMP‐11 showed a direct correlation with the levels of in vivo tumor cell invasiveness. Conversely, secretion of MMP‐3 correlated closely with tumorigenicity and invasiveness. In vitro tumor cell invasiveness was significantly reduced after incubation with the metalloproteinase inhibitor GM6001. This positive correlation between MMP‐3 and the depth of tracheal wall penetration led us to conclude that the invasive properties of brain tumor cells may be due to the direct or indirect proteolytic effects of MMP‐3 on extracellular matrix (ECM) macromolecules and that this enzyme might be a potential target for future therapies. © 2003 Wiley‐Liss, Inc.
Time trends in cancer mortality in China: 1987–1999
Authors: Yang Ling , Parkin Donald M. , Li Liandi , Chen Yude
Published: July 2003

A first analysis of time trends in cancer mortality in China at the national level is presented. Using a joinpoint regression model, based on data from a national mortality routine reporting system in China (CHIS), time trends in mortality for 9 major cancers are analyzed. Between 1987 and 1999, the age‐standardized mortality rates for all cancers combined declined slightly in rural areas but have increased since 1996 in urban areas. The mortality rates for cancers in oesophagus, stomach, cervix uteri, leukaemia (except for urban males after 1996) and nasopharynx declined, while lung cancer and female breast cancer showed significant increasing trends in both urban and rural areas and for both sexes. Cancers of the colon‐rectum and liver had different trends in mortality in urban and rural populations. The trends in age‐specific mortality rates suggest some different trends in the younger population, which may presage future overall trends, for example, increasing mortality from cancer of the cervix. The observed trends primarily reflect the dramatic changes in socioeconomic circumstances and lifestyles in China in the last 2 decades. Tobacco smoking remains a major problem, with increases in mortality from lung cancer. The improvements in socioeconomic status, diet and nutrition may be responsible for the declining risk of some cancers (oesophagus, stomach and nasopharynx), while increasing the risk for others (breast and colon‐rectum). Screening programs (especially for cervix cancer), and more available and better facilities for cancer therapy, may have helped to reduce mortality for several cancers. The large increases in the absolute number of deaths that resulted from the increasing and aging population are much more important in determining the future cancer burden than any changes due to change in risk, emphasizing the increasing importance of cancer as a health problem in the 21st century in China. © 2003 Wiley‐Liss, Inc.
Expression of peroxisome‐proliferator activated receptor‐gamma (PPARγ) and the PPARγ co‐activator, PGC‐1, in human breast cancer correlates with clinical outcomes
Authors: Jiang Wen G. , Douglas‐Jones Anthony , Mansel Robert E.
Published: July 2003

Peroxisome‐proliferator activated receptor‐gamma (PPARγ) belongs to a family of nuclear receptors and acts as receptor for peroxisome‐proliferators, steroids, retinoic acids, and polyunsaturated fatty acids. Our study examined the transcript levels of peroxisome‐proliferator activated receptor‐gamma (PPARγ) and its co‐activator (PGC‐1) in a cohort of patients with breast cancer. An invasive breast cancer cell, MDA MB 231 exhibited lower level of expression of PPARγ, compared to non‐invasive MCF‐7. Breast cancer tissues (n= 120) exhibited a lower level of PPARγ mRNA compared to normal tissues (n= 25,p= 0.05). No difference, however, was seen with PGC‐1. Although the levels of PPARγ and PGC‐1 did not correlate with nodal involvement and grade, significantly lower levels of PPARγ were seen in TNM3 and TNM4 tumors and from patients with local recurrence and those who died of breast cancer. Lowest level of PGC‐1 was also seen in TNM3 and TNM4 tumors and patients who died of breast cancer. We conclude that there is aberrant expression of PPARγ and its co‐activator, PGC‐1, in human breast cancer and low levels of these molecules in cancer tissues are associated with poor clinical outcomes. © 2003 Wiley‐Liss, Inc.
A warm welcome for destination quality brands: the example of the Pays Cathare region
Authors: Woods Megan , Deegan Jim
Published: July 2003

In this paper, the salient complexities characterising quality management at the tourism destination are outlined, and in light of these, a number of quality principles are deemed particularly appropriate for the further investigation of destination quality management (DQM). The complexities include the significant number of services provided at the destination, the highly fragmented nature of the tourism destination product and the large number of small businesses that go to comprise this product. General principles are drawn from the SERVQUAL, Kano and EFQM Business Excellence models in order to provide a tentative framework for investigating how one destination has striven to overcome these challenges. The example of the Pays Cathare Region in southern France, which has been recognised by the European Commission as an example of best practice in integrated quality management (IQM), shows how these quality tenets can be translated from the theoretical framework into actual practice by means of its destination quality brand. Copyright © 2003 John Wiley &Sons, Ltd.
Transitional economy tourism: German travel consumers' perceptions of Lithuania
Authors: Clottey Birute , Lennon Ron
Published: July 2003

This paper examines the current status of tourism in Lithuania as well as potential German tourists' perceptions of Lithuania as a tourist destination. As tourism is an important source of foreign exchange and provides jobs for a large number of people, the Lithuanian Government is quite interested in increasing the number of tourists visiting the country. Data gathered at the International Tourism Exchange in Berlin was analysed and recommendations made concerning marketing techniques that could be used to increase tourism from the European Union and other western countries. Copyright © 2003 John Wiley &Sons, Ltd.
In vivo autofluorescence spectroscopy of oral premalignant and malignant lesions: Distortion of fluorescence intensity by submucous fibrosis
Authors: Tsai Tsuimin , Chen Hsin‐Ming , Wang Chih‐Yu , Tsai Jui‐Chang , Chen Chin‐Tin , Chiang Chun‐Pin
Published: July 2003

Background and Objectives

To test whether autofluorescence spectroscopy can be used for the diagnosis of oral neoplasia in a high‐risk population, we characterized the in vivo autofluorescence spectra from oral submucous fibrosis (OSF) lesions and oral premalignant and malignant lesions in both OSF and non‐OSF patients.

Study Design/Materials and Methods

Autofluore scence emission spectra were measured under the excitation wavelength of 330 nm, using a Xenon lamp‐based fluorospectrometer coupled to a handheld optical fiber probe. Autofluorescence spectroscopies were analyzed among patients with OSF lesions, and oral lesions of epithelial hyperkeratosis (EH), epithelial dysplasia (ED), and squamous cell carcinomas (SCC) and normal oral mucosa (NOM) of healthy volunteers.

Results

We found that the most intensely autofluorescence emission peaks occurred at 380 nm and 460 nm. For comparing the spectral patterns among different groups of oral lesions and NOM, ratios of the area under the spectrum of 460±10 nm to that under the spectrum of 380±10 nm (denoted as A460±10nm/A380±10nm) were calculated. The mean ratio values increased gradually from OSF to NOM, to EH and ED, and to SCC. The ANOVA test showed significant differences in the ratio value among all categories of samples (P<0.01). On the other hand, we found that EH, ED, and SCC lesions on OSF patients had distorted autofluorescence intensity. The mean ratio values of EH, ED, and SCC between non‐OSF and OSF patients show significant differences. Furthermore, an ANOVA test showed NOM is not distinguishable from EH and ED lesions on oral fibrotic mucosa (P>0.05).

Conclusions

Autofluorescence spectroscopy can be used to diagnose EH, ED, and SCC lesions in non‐OSF patients but not in OSF patients. Lasers Surg. Med. 33:40–47, 2003. © 2003 Wiley‐Liss, Inc.
Thermal response of human skin epidermis to 595‐nm laser irradiation at high incident dosages and long pulse durations in conjunction with cryogen spray cooling: An ex‐vivo study
Authors: Dai Tianhong , Pikkula Brian M. , Tunnell James W. , Chang David W. , Anvari Bahman
Published: July 2003

Background and Objectives

Improved laser treatment of cutaneous hypervascular lesions is expected by utilizing higher incident dosages, longer pulse durations and longer wavelengths than those currently used in clinical settings. However, simply increasing the incident dosage will also increase the risk of nonspecific thermal injury to the epidermis due to light absorption by melanin. In this study, we investigated the thermal response of human skin epidermis to 595‐nm wavelength laser irradiation at high incident dosages (up to 20 J/cm2) and long pulse durations (up to 40 milliseconds) in conjunction with cryogen spray cooling (CSC) using ex‐vivo human skin samples.

Study Design/Materials and Methods

The Candela V‐beam™ laser (595‐nm wavelength) was used in the experiments. Ex‐vivo human skin samples (Fitzpatrick types I–VI) were irradiated at the incident dosages D0 = 4, 6, 10, 15, and 20 J/cm2, laser pulse durations τlaser = 1.5, 10, and 40 milliseconds, without and with CSC (refrigerant‐134A, spurt duration τCSC = 100 milliseconds). Thermal injury to the epidermis was evaluated by histological observations.

Results

Under the same incident dosage, longer pulse durations led to reduced thermal injury to the epidermis. Without CSC, no demonstrable thermal injury to the epidermis was observed in skin types I–II irradiated at the incident dosage as high as 15 J/cm2, and in skin types III–IV at 10 J/cm2. When CSC was applied, no evidence of thermal injury to the epidermis was present in skin types I–II even when irradiated at the maximum available incident dosage of the laser system (20 J/cm2). In skin types III–IV, no demonstrable thermal injury to the epidermis was observed when using incident dosage as high as 15 J/cm2 in conjunction with CSC. In skin type VI, thermal injury to the epidermis could not be avoided even at the setting D0 = 4 J/cm2, τlaser = 40 milliseconds in conjunction with CSC.

Conclusions

For a given incident dosage, longer pulse durations help reduce thermal injury to the epidermis. When a 100‐millisecond cryogen spurt is applied, thermal injury to the epidermis can be prevented in ex‐vivo skin types I–IV when irradiated at higher incident dosages (15–20 J/cm2) than those currently used in clinical settings. Further studies on optimizing the CSC parameters in conjunction with the laser irradiation parameters are needed to protect skin types V–VI from thermal injury to the epidermis. Lasers Surg. Med. 33:16–24, 2003. © 2003 Wiley‐Liss, Inc.
Arterial wall strength after endovascular photodynamic therapy
Authors: Gabeler Edward E.E. , van Hillegersberg Richard , Sluiter Wim , Kliffen Mike , Statius van Eps Randolph G. , Honkoop Jan , Carlier Stephane G. , van Urk Hero
Published: July 2003

Background and Objectives

Vascular photodynamic therapy (PDT) inhibits intimal hyperplasia (IH) induced by angioplasty in rat iliac arteries by eradicating the proliferating smooth muscle cells. This process may jeopardise the structure and strength of the arterial wall, reflected by a decreased bursting pressure.

Study design/Materials and Methods

Thirty male Wistar rats of 250–300 g were subdivided into 3 groups (n = 10). In all groups, IH was induced by balloon injury (BI). One experimental group received PDT at 50 J/cm diffuser length, the other group at 100 J/cm diffuser length. The third group served as control group and received no PDT. In half of each group the bursting pressure was analyzed after 2 hours (n = 5), in the other half after 1 year.

Results

Two hours after the procedure the bursting pressure was 3.37 ± 0.58 (±SEM) bar in the BI + PDT 50 and 3.96 ± 0.43 bar in the BI + PDT 100 group, compared to 2.20 ± 0.27 bar in the BI group (P < 0.05). After 1 year these values were 3.18 ± 0.87 bar in the BI + PDT 50 (P < 0.05) and 2.02 ± 0.31 bar in the BI + PDT 100 group, compared to 2.10 ± 0.30 bar in the BI group (NS). In the BI + PDT 100 group, 3 out of 5 rats appeared to have aneurysmal dilatation after 1 year.

Conclusions

Endovascular PDT increases the arterial wall strength as measured by the bursting pressure at short‐term. After 1 year, wall strength is not diminished as measured by bursting pressure, but aneurysmal dilatation nevertheless developed with 100 J/cm · dl. This may limit the use of high energy PDT. Lasers Surg. Med. 33:8–15, 2003. © 2003 Wiley‐Liss, Inc.
Improved quality of life after XeCl excimer transmyocardial laser revascularization: Results of a randomized trial
Authors: Huikeshoven Menno , van der Sloot Jos A.P. , Tukkie Raymond , van Gemert Martin J.C. , Tijssen Jan G.P. , Beek Johan F.
Published: July 2003

Background and Objectives

We assessed quality of life (QOL) after XeCl transmyocardial laser revascularization (TMLR).

Study Design/Materials and Methods

Thirty patients were randomized to receive XeCl excimer TMLR or optimal cardiac medication (controls). QOL was assessed at baseline, 1, 3, 6, and 12 months using three different questionnaires: The Medical Outcomes Study Short Form‐24 (MOS SF‐24), the EuroQol Standardized Questionnaire, and the Seattle Angina Questionnaire (SAQ). The primary outcome measure was the change in score between baseline and 12 months.

Results

TMLR patients scored significantly better compared to controls in the MOS SF‐24 social functioning, energy, general health, and bodily pain domains, in the EuroQol usual activity domain and the EuroQol Visual Analogue Scale, and in the SAQ physical limitation, angina frequency and disease perception domains.

Conclusions

QOL significantly improved after XeCl excimer TMLR compared to medication. These results are similar to reported improvements in QOL after CO2 and Ho:YAG TMLR. Lasers Surg. Med. 33:1–7, 2003. © 2003 Wiley‐Liss, Inc.
Nonablative laser and light treatments: Histology and tissue effects—A Review
Authors: Alam Murad , Hsu Te‐Shao , Dover Jeffrey S. , Wrone David A. , Arndt Kenneth A.
Published: July 2003

Background and Objectives

Nonablative laser and light treatments have largely replaced ablative laser therapy in clinical use for the improvement of the visible signs of cutaneous photoaging, including rhytides, vascular lesions, and pigmentation. However, the mechanisms underlying the reported clinical efficacy of nonablative treatments are not well‐understood. The purpose of this analysis is to critically evaluate what is known about histologic and tissue effects of nonablative laser therapy and suggest future directions for research.

Study Design/Materials and Methods

This is a review of the English language literature pertaining to nonablative laser and light treatments available through MEDline (1995–2002), and unpublished reports presented at major national meetings. Only studies that included harvesting and analysis of tissue samples are included.

Results and Conclusions

(a) Thermal injury to the dermis in association with epidermal cooling most likely affects the dermal vasculature, which initiates a cascade of inflammatory events that includes fibroblastic proliferation and apparent up‐regulation of collagen expression; (b) There is no indication that nonablative treatments are harmful or able to induce skin cancer; (c) It is possible that the horizontally distributed collagen reported after nonablative treatments is a “microscar,” an enlarged Grenz sone associated with repetitive photo‐induced trauma; (d) Further research is needed to elucidate the biophysical mechanisms underlying nonablative treatment, as well as to distinguish the utility of different wavelengths on epidermal and dermal improvement. Lasers Surg. Med. 33:30–39, 2003. © 2003 Wiley‐Liss, Inc.
Quality of GPs' referral letters to diabetes secondary care
Authors: Syed AA , Large DM
Published: July 2003

Good quality referral information enables appropriate triage and the best use of scarce secondary care resources. We evaluated the quality of GPs' referral letters to our district general hospital diabetes centre to identify types of information that receive the highest and the least priority with the objective of developing constructive feedback.

Eighty‐one letters from 51 GPs, excluding requests for reassessment, emergency inpatient care or non‐diabetic concerns, were evaluated on 24 parameters of varying clinical importance and categorised as ‘low’(0.0–9.9), ‘mid’(10.0–19.9) or ‘high’ (20.0–30.0) scoring (total 30.0 points).

Total scores ranged from 4.5 to 30 (mean 13.3). Mean per cent scores (95% confidence intervals), for selected parameters were: home glucose monitoring 29.6 (19.9 to 39.3); HbA1c 47.8 (38.3 to 57.4); retinal surveillance 32.1 (21.9 to 42.3) and complications 30.9 (20.9 to 40.8); microalbuminuria 28.4 (18.4 to 38.3) and renal complications 23.5 (14.3 to 32.6); foot care 19.8 (11.0 to 28.5) and complications 24.1 (14.9 to 33.2); blood pressure 41.4 (30.9 to 51.8); bodyweight 30.3 (20.9 to 39.6). Low‐scoring letters (32.1%) regularly provided five items of information, mid‐scoring (51.9%) 10 items and high‐scoring (16.1%) 20 items.

Overall, letters were lacking in information regarding surveillance, recognition and management of microangiopathy, blood pressure, body weight, home glucose monitoring and biochemistry. High‐scoring letters reflected good insight into the care of people with diabetes. Copyright © 2003 John Wiley & Sons, Ltd.
Ensuring the quality of diabetes care: Use of the QUAD‐CAT model and Alphabet Strategy in clinical practice
Authors: Goenka N , Panja S , James D , Shaikh S , Morrissey J , Patel V
Published: July 2003

There are wide regional variations in the quality and provision of diabetes care. The pressure is on health care providers to deliver care of the highest quality. The Quality of Care Diabetes Assessment Tool (QUAD‐CAT) was developed to benchmark the care provided in primary and secondary care, based on the American Diabetes Association (ADA) model.

We studied data from a random selection of 25 diabetic patients from 10 primary care centres and 100 diabetic patients from George Eliot Hospital diabetes clinic. Data were collected based on the template of the Alphabet Strategy for managing diabetes, for various parameters, including HbA1c, blood pressure, eye and foot examination, nephropathy assessment, lipid profile and aspirin use. A patient questionnaire was included to assess the subjective quality of service.

Points were allocated based on the ADA scoring system. In order for a centre to be accredited, 80 out of 110 points were required. The overall points range was 40–95, with three practices accredited. There was a wide variation in performance in the key measures assessed between the practices.

In conclusion, QUAD‐CAT provides an easily conducted and well‐accepted tool to evaluate the quality of clinical care and patient's perception of diabetes services Copyright © 2003 John Wiley & Sons, Ltd.