bluuebunny/crossref_metadata_2025 huggingface dataset:
Actin Cytoskeletal Reorganizations and Coreceptor-Mediated Activation of Rac during Human Immunodeficiency Virus-Induced Cell Fusion
Authors: Pontow S. E. , Heyden N. Vander , Wei S. , Ratner L.
Published: June 2004

The membrane fusion events which initiate human immunodeficiency virus type 1 (HIV-1) infection and promote cytopathic syncytium formation in infected cells commence with the binding of the HIV envelope glycoprotein (Env) to CD4 and an appropriate coreceptor. Here, we show that HIV Env-coreceptor interactions activate Rac-1 GTPase and stimulate the actin filament network reorganizations that are requisite components of the cell fusion process. Disrupting actin filament dynamics with jasplakinolide or latrunculin A arrested fusion at a late step in the formation of Env-CD4-coreceptor complexes. Time-lapse confocal microscopy of living cells revealed vigorous activity of actin-based, target cell membrane extensions at the target cell-Env-expressing cell interface. The expression of dominant-negative forms of actin-regulating Rho-family GTPases established that HIV Env-mediated syncytium formation relies on Rac-1 but not on Cdc42 or Rho activation in target cells. Similar dependencies were found when cell fusion was induced by Env expressed on viral or cellular membranes. Additionally, Rac activity was specifically upregulated in a coreceptor-dependent manner in fusion reaction cell lysates. These results define a role for HIV Env-coreceptor interactions in activating the cellular factors essential for virus-cell and cell-cell fusion and provide evidence for the participation of pertussis toxin-insensitive signaling pathways in HIV-induced membrane fusion.
Prion Infection of Epithelial Rov Cells Is a Polarized Event
Authors: Paquet Sophie , Sabuncu Elifsu , Delaunay Jean-Louis , Laude Hubert , Vilette Didier
Published: June 2004

During prion infections, the cellular glycosylphosphatidylinositol-anchored glycoprotein PrP is converted into a conformational isoform. This abnormal conformer is thought to recruit and convert the normal cellular PrP into a likeness of itself and is proposed to be the infectious agent. We investigated the distribution of the PrP protein on the surface of Rov cells, an epithelial cell line highly permissive to prion multiplication, and we found that PrP is primarily expressed on the apical side. We further show that prion transmission to Rov cells is much more efficient if infectivity contacts the apical side, indicating that the apical and basolateral sides of Rov cells are not equally competent for prion infection and adding prions to the list of the conventional infectious agents (viruses and bacteria) that infect epithelial cells in a polarized manner. These data raise the possibility that apically expressed PrP may be involved in this polarized process of infection. This would add further support for a crucial role of PrP at the cell surface in prion infection of target cells.
Intracellular Trafficking of Gag and Env Proteins and Their Interactions Modulate Pseudotyping of Retroviruses
Authors: Sandrin Virginie , Muriaux Delphine , Darlix Jean-Luc , Cosset François-Loïc
Published: June 2004

Glycoproteins derived from most retroviruses and from several families of enveloped viruses can form infectious pseudotypes with murine leukemia virus (MLV) and lentiviral core particles, like the MLV envelope glycoproteins (Env) that are incorporated on either virus type. However, coexpression of a given glycoprotein with heterologous core proteins does not always give rise to highly infectious viral particles, and restrictions on pseudotype formation have been reported. To understand the mechanisms that control the recruitment of viral surface glycoproteins on lentiviral and retroviral cores, we exploited the fact that the feline endogenous retrovirus RD114 glycoprotein does not efficiently pseudotype lentiviral cores derived from simian immunodeficiency virus, whereas it is readily incorporated onto MLV particles. Our results indicate that recruitment of glycoproteins by the MLV and lentiviral core proteins occurs in intracellular compartments and not at the cell surface. We found that Env and core protein colocalization in intracytoplasmic vesicles is required for pseudotype formation. By investigating MLV/RD114 Env chimeras, we show that signals in the cytoplasmic tail of either glycoprotein differentially influenced their intracellular localization; that of MLV allows endosomal localization and hence recruitment by both lentiviral and MLV cores. Furthermore, we found that upon membrane binding, MLV core proteins could relocalize Env glycoproteins in late endosomes and allow their incorporation on viral particles. Thus, intracellular colocalization, as well as interactions between Env and core proteins, may influence the recruitment of the glycoprotein onto viral particles and generate infectious pseudotyped viruses.
Receptor (CD155)-Dependent Endocytosis of Poliovirus and Retrograde Axonal Transport of the Endosome
Authors: Ohka Seii , Matsuda Norie , Tohyama Koujiro , Oda Toshiyuki , Morikawa Masato , Kuge Shusuke , Nomoto Akio
Published: June 2004

Poliovirus (PV), when injected intramuscularly into the calf, is incorporated into the sciatic nerve and causes an initial paralysis of the inoculated limb in transgenic mice carrying the human PV receptor (hPVR/CD155) gene. Here, we demonstrated by using an immunoelectron microscope that PV particles exist on vesicle structures in nerve terminals of neuromuscular junctions. We also demonstrated in glutathione
S
-transferase pull-down experiments that the dynein light chain, Tctex-1, interacts directly with the cytoplasmic domain of hPVR. In the axons of differentiated rat PC12 cells transfected with expression vectors for hPVRs, vesicles composed of PV and hPVRα, as well as a mutant hPVRα (hPVRMα) that had a reduced ability to bind Tctex-1, colocalized with Tctex-1. However, vesicles containing PV, dextran, and hPVRα had only retrograde motion, while those containing PV, dextran, and hPVRMα had anterograde or retrograde motion. Topical application of the antimicrotubule agent vinblastine to the sciatic nerve reduced the amount of virus transported from the calf to the spinal cord. These results suggest that direct efficient interaction between the cytoplasmic domain and Tctex-1 is essential for the efficient retrograde transport of PV-containing vesicles along microtubules in vivo.
E1
∧
E4 Protein of Human Papillomavirus Type 16 Associates with Mitochondria
Authors: Raj Kenneth , Berguerand Samuel , Southern Shirley , Doorbar John , Beard Peter
Published: June 2004

The human papillomavirus (HPV) E1
∧
E4 protein is the most abundantly expressed viral protein in HPV-infected epithelia. It possesses diverse activities, including the ability to bind to the cytokeratin network and to DEAD-box proteins, and in some cases induces the collapse of the former. E1
∧
E4 is also able to prevent the progression of cells into mitosis by arresting them in the G
2
phase of the cell cycle. In spite of these intriguing properties, the role of this protein in the life cycle of the virus is not clear. Here we report that after binding to and collapsing the cytokeratin network, the HPV type 16 E1
∧
E4 protein binds to mitochondria. When cytokeratin is not present in the cell, E1
∧
E4 appears associated with mitochondria soon after its synthesis. The leucine cluster within the N-terminal portion of the E1
∧
E4 protein is pivotal in mediating this association. After the initial binding to mitochondria, the E1
∧
E4 protein induces the detachment of mitochondria from microtubules, causing the organelles to form a single large cluster adjacent to the nucleus. This is followed by a severe reduction in the mitochondrial membrane potential and an induction of apoptosis. HPV DNA replication and virion production occur in terminally differentiating cells which are keratin-rich, rigid squamae that exfoliate after completion of the differentiation process. Perturbation of the cytokeratin network and the eventual induction of apoptotic properties are processes that could render these unyielding cells more fragile and ease the exit of newly synthesized HPVs for subsequent rounds of infection.
Small Compounds Targeted to Subunit Interfaces Arrest Maturation in a Nonenveloped, Icosahedral Animal Virus
Authors: Lee Kelly K. , Tang Jinghua , Taylor Derek , Bothner Brian , Johnson John E.
Published: June 2004

Nudaurelia
ω
capensis
virus (NωV) capsids were previously characterized in two morphological forms, a T=4, 485-Å-diameter round particle with large pores and a tightly sealed 395-Å icosahedrally shaped particle with the same quasi-symmetric surface lattice. The large particle converts to the smaller particle when the pH is lowered from 7.6 to 5, and this activates an autocatalytic cleavage of the viral subunit at residue 570. Here we report that both 1-anilino-8 naphthalene sulfonate (ANS) and the covalent attachment of the thiol-reactive fluorophore, maleimide-ANS (MIANS), inhibit the structural transition and proteolysis at the lower pH. When ANS is exhaustively washed from the particles, the maturation proceeds normally; however, MIANS-modified particles are still inhibited after the same washing treatment, indicating that covalent attachment targets MIANS to a critical location for inhibition. Characterization of the low-pH MIANS product by electron cryo-microscopy (cryo-EM) and image reconstruction demonstrated a morphology intermediate between the two forms previously characterized. A pseudoatomic model of the intermediate configuration was generated by rigid body refinement of the X-ray structure of the subunits (previously determined in the assembled capsid) into the cryo-EM density, allowing a quantitative description of the inhibited intermediate and a hypothesis for the mechanism of the inhibition.
Gene Transduction and Cell Entry Pathway of Fiber-Modified Adenovirus Type 5 Vectors Carrying Novel Endocytic Peptide Ligands Selected on Human Tracheal Glandular Cells
Authors: Gaden Florence , Franqueville Laure , Magnusson Maria K. , Hong Saw See , Merten Marc D. , Lindholm Leif , Boulanger Pierre
Published: June 2004

Monolayers of cystic fibrosis transmembrane conductance regulator (CFTR)-deficient human tracheal glandular cells (CF-KM4) were subjected to phage biopanning, and cell-internalized phages were isolated and sequenced, in order to identify CF-KM4-specific peptide ligands that would confer upon adenovirus type 5 (Ad5) vector a novel cell target specificity and/or higher efficiency of gene delivery into airway cells of patients with cystic fibrosis (CF). Three different ligands, corresponding to prototypes of the most represented families of phagotopes recovered from intracellular phages, were designed and individually inserted into Ad5-green fluorescent protein (GFP) (AdGFP) vectors at the extremities of short fiber shafts (seven repeats [R7]) terminated by scissile knobs. Only one vector, carrying the decapeptide GHPRQMSHVY (abbreviated as QM10), showed an enhanced gene transduction of CF-KM4 cells compared to control nonliganded vector with fibers of the same length (AdGFP-R7-knob). The enhancement in gene transfer efficiency was not specific to CF-KM4 cells but was observed in other mammalian cell lines tested. The QM10-liganded vector was referred to as AdGFP-QM10-knob in its knobbed version and as AdGFP-QM10 in its proteolytically deknobbed version. AdGFP-QM10 was found to transduce cells with a higher efficiency than its knob-bearing version, AdGFP-QM10-knob. Consistent with this, competition experiments indicated that the presence of knob domains was not an absolute requirement for cell attachment of the QM10-liganded vector and that the knobless AdGFP-QM10 used alternative cell-binding domains on its capsid, including penton base capsomer, via a site(s) different from its RGD motifs. The QM10-mediated effect on gene transduction seemed to take place at the step of endocytosis in both quantitative and qualitative manners. Virions of AdGFP-QM10 were endocytosed in higher numbers than virions of the control vector and were directed to a compartment different from the early endosomes targeted by members of species C Ad. AdGFP-QM10 was found to accumulate in late endosomal and low-pH compartments, suggesting that QM10 acted as an endocytic ligand of the lysosomal pathway. These results validated the concept of detargeting and retargeting Ad vectors via our deknobbing system and redirecting Ad vectors to an alternative endocytic pathway via a peptide ligand inserted in the fiber shaft domain.
Influence of N-Glycans on Processing and Biological Activity of the Nipah Virus Fusion Protein
Authors: Moll Markus , Kaufmann Andreas , Maisner Andrea
Published: June 2004

Nipah virus
(NiV), a new member of the
Paramyxoviridae
, codes for a fusion (F) protein with five potential N-glycosylation sites. Because glycans are known to be important structural components affecting the conformation and function of viral glycoproteins, we analyzed the effect of the deletion of N-linked oligosaccharides on cell surface transport, proteolytic cleavage, and the biological activity of the NiV F protein. Each of the five potential glycosylation sites was removed either individually or in combination, revealing that four sites are actually utilized (g2 and g3 in the F
2
subunit and g4 and g5 in the F
1
subunit). While the removal of g2 and/or g3 had no or little effect on cleavage, surface transport, and fusion activity, the elimination of g4 or g5 reduced the surface expression by more than 80%. Similar to a mutant lacking all N-glycans, g4 deletion mutants in which the potential glycosylation site was destroyed by introducing a glycine residue were neither cleaved nor transported to the cell surface and consequently were not able to mediate cell-to-cell fusion. This finding indicates that in the absence of g4, the amino acid sequence around position 414 is important for folding and transport.
CHARACTERIZATION OF NUCLEAR IMAGES BASED ON ANALYSIS OF FRACTIONAL SUMMATION SYSTEMS
Authors: WU HAI-SHAN , EINSTEIN ANDREW J. , DELIGDISCH LIANE , KALIR TAMARA , GIL JOAN
Published: June 2004

While frequency-based methods for the characterization of fractals are popular and effective in many applications, they have limitations when applied to irregularly shaped images, such as nuclear images. The irregularity renders texture characterization by frequency domain methods, based upon Fourier transform, problematic. To address this situation, this paper presents an algorithm based upon the signal analysis in the spatial domain. An autocovariance function can be estimated regardless of the shape and size of regions where the image is defined. As in the continuous fractional Brownian motion (FBM) that results from inputting white noise into a specific fractional integral system, a discrete FBM can be related to white noise by a specific fractional summation system (FSS) that is linear, causal and shift-invariant. Although the method of direct sampling is not valid for converting a continuous fractional integral to a discrete fractional summation, discrete fractional summations similar to the sampled system functions can be obtained through an iterative process. While the continuous system function of a fractional integral is linear in the frequency domain when plotted in log-log scales, unfortunately, it is not true for the comparable discrete system function. The discrete system function is actually approximately linear in the log-log scales over a very limited range. The slope of the straight line that approximates the function curve in the mean-square-error (MSE) sense in a specific time range provides a description of the autocovariance function that reveals the statistical relations among the local textures. Applications to characterization of ovary nuclear images in groups of normal, atypical and cancer cases are studied and presented.
MULTIFRACTAL ANALYSIS OF ADSORBATE IN A CATALYZED SURFACE REACTION
Authors: LUQUE J. J. , GÓMEZ A. , CÓRDOBA A.
Published: June 2004

The use of multifractals in heterogeneous chemistry has proven useful in the characterization of some complex phenomena. This paper proposes a multifractal analysis in order to study the distribution of adsorbed particles for a reaction of a monomer and a dimer that dissociates, both of which are adsorbed on a surface and react. For a range of a control parameter, there is a steady reactive window that changes when adsorbate-adsorbate lateral interaction is considered. τ(q) and f(α) for different values of control parameter and interactions are calculated, studying distribution of adsorbed particles in relation to multifractal properties.
Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate secretion in rats
Authors: Aoi Masako , Aihara Eitaro , Nakashima Masato , Takeuchi Koji
Published: June 2004

We examined, by using a specific PGE receptor subtype EP4 agonist and antagonist, the involvement of EP4 receptors in duodenal HCO3− secretion induced by PGE2 and mucosal acidification in rats. Mucosal acidification was achieved by exposing a duodenal loop to 10 mM HCl for 10 min, and various EP agonists were given intravenously 10 min before the acidification. Secretion of HCO3− was dose-dependently stimulated by AE1-329 (EP4 agonist), the maximal response being equivalent to that induced by sulprostone (EP1/EP3 agonist) or PGE2. The stimulatory action of AE1-329 and PGE2 but not sulprostone was attenuated by AE3-208, a specific EP4 antagonist. This antagonist also significantly mitigated the acid-induced HCO3− secretion. Coadministration of sulprostone and AE1-329 caused a greater secretory response than either agent alone. IBMX potentiated the stimulatory action of both sulprostone and AE1-329, whereas verapamil mitigated the effect of sulprostone but not AE1-329. Chemical ablation of capsaicin-sensitive afferent neurons did not affect the response to any of the EP agonists used. We conclude that EP4 receptors are involved in the duodenal HCO3− response induced by PGE2 or acidification in addition to EP3 receptors. The process by which HCO3− is secreted through these receptors differs regarding second-messenger coupling. Stimulation through EP4 receptors is mediated by cAMP, whereas that through EP3 receptors is regulated by both cAMP and Ca2+; yet there is cooperation between the actions mediated by these two receptors. The neuronal reflex pathway is not involved in stimulatory actions of these prostanoids.
Inflammation and Cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation
Authors: Itzkowitz Steven H. , Yio Xianyang
Published: June 2004

Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer. To date, no known genetic basis has been identified to explain colorectal cancer predisposition in these inflammatory bowel diseases. Instead, it is assumed that chronic inflammation is what causes cancer. This is supported by the fact that colon cancer risk increases with longer duration of colitis, greater anatomic extent of colitis, the concomitant presence of other inflammatory manifestations such as primary sclerosing cholangitis, and the fact that certain drugs used to treat inflammation, such as 5-aminosalicylates and steroids, may prevent the development of colorectal cancer. The major carcinogenic pathways that lead to sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also occur in colitis-associated colorectal cancers. Unlike normal colonic mucosa, however, inflamed colonic mucosa demonstrates abnormalities in these molecular pathways even before any histological evidence of dysplasia or cancer. Whereas the reasons for this are unknown, oxidative stress likely plays a role. Reactive oxygen and nitrogen species produced by inflammatory cells can interact with key genes involved in carcinogenic pathways such as p53, DNA mismatch repair genes, and even DNA base excision-repair genes. Other factors such as NF-κB and cyclooxygenases may also contribute. Administering agents that cause colitis in healthy rodents or genetically engineered cancer-prone mice accelerates the development of colorectal cancer. Mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization. These observations offer compelling support for the role of inflammation in colon carcinogenesis.
Gastric distension-induced release of 5-HT stimulates c-fos expression in specific brain nuclei via 5-HT3 receptors in conscious rats
Authors: Mazda Takayuki , Yamamoto Hiroshi , Fujimura Masaki , Fujimiya Mineko
Published: June 2004

We examined c- fos expression in specific brain nuclei in response to gastric distension and investigated whether 5-HT released from enterochromaffin (EC) cells was involved in this response. The role of 5-HT3 receptors in this mechanism was also addressed. Release of 5-HT was examined in an ex vivo-perfused stomach model, whereas c- fos expression in brain nuclei induced by gastric distension was examined in a freely moving conscious rat model. Physiological levels of gastric distension stimulated the vascular release of 5-HT more than luminal release of 5-HT, and induced c- fos expression in the nucleus of the solitary tract (NTS), area postrema (AP), paraventricular nucleus (PVN), and supraoptic nucleus (SON). The c- fos expression in all these brain nuclei was blocked by truncal vagotomy as well as by perivagal capsaicin treatment, suggesting that vagal afferent pathways may mediate this response. Intravenous injection of 5-HT3 receptor antagonist granisetron blocked c- fos expression in all brain nuclei examined, although intracerebroventricular injection of granisetron had no effect, suggesting that 5-HT released from the stomach may activate 5-HT3 receptors located in the peripheral vagal afferent nerve terminals and then induce brain c- fos expression. c- fos Positive cells in the NTS were labeled with retrograde tracer fluorogold injected in the PVN, suggesting that neurons in the NTS activated by gastric distension project axons to the PVN. The present results suggest that gastric distension stimulates 5-HT release from the EC cells and the released 5-HT may activate 5-HT3 receptors located on the vagal afferent nerve terminals in the gastric wall leading to neuron activation in the NTS and AP and subsequent activation of neurons in the PVN and SON.
Mrp2 is involved in benzylpenicillin-induced choleresis
Authors: Ito Kousei , Koresawa Tomokazu , Nakano Koichi , Horie Toshiharu
Published: June 2004

Benzylpenicillin (PCG; 180 μmol/kg), a classic β-lactam antibiotic, was intravenously given to Sprague-Dawley (SD) rats and multidrug resistance-associated protein 2 (Mrp2)-deficient Eisai hyperbilirubinemic rats (EHBR). A percentage of the [3H]PCG was excreted into the bile of the rats within 60 min (SD rats: 31.7% and EHBR: 4.3%). Remarkably, a transient increase in the bile flow (∼2-fold) and a slight increase in the total biliary bilirubin excretion were observed in SD rats but not in the EHBR after PCG administration. This suggests that the biliary excretion of PCG and its choleretic effect are Mrp2-dependent. Positive correlations were observed between the biliary excretion rate of PCG and bile flow ( r2= 0.768) and more remarkably between the biliary excretion rate of GSH and bile flow ( r2= 0.968). No ATP-dependent uptake of [3H]PCG was observed in Mrp2-expressing Sf9 membrane vesicles, whereas other forms of Mrp2-substrate transport were stimulated in the presence of PCG. GSH efflux mediated by human MRP2 expressed in Madin-Darby canine kidney II cells was enhanced in the presence of PCG in a concentration-dependent manner. In conclusion, the choleretic effect of PCG is caused by the stimulation of biliary GSH efflux as well as the concentrative biliary excretion of PCG itself, both of which were Mrp2 dependent.
Vision for Converging Technologies and Future Society
Authors: BOND PHILLIP J.
Published: June 2004

Abstract: This brief presentation places the challenges of nanotechnology in a political, social, and economic context.
Integrative Technology for the Twenty‐First Century
Authors: MONTEMAGNO CARLO D.
Published: June 2004

Abstract: Presented is the concept of Integrative Technology, the intersection of the precision assembly of matter (nanotechnology), coupled with the functional building blocks of nature (biotechnology), and fused by the network flow of spatiotemporal information (informatics). The power of Integrative Technology is illuminated through an illustrative example; the engineering of nano‐sized excitable vesicles with the ability to intrinsically process information. The fusion of the tools of nanotechnology and biotechnology to produce excitable vesicles is described, as is the mechanics of information flow that ultimately lead to the manifestations of emergent higher‐order behavior. Finally, the potential of using systems engineered and produced from nanoscale components to create complex systems and materials that manifest embedded functional behavior is discussed.
Early Convergence Research and Education Supported by the National Science Foundationa
Authors: BAINBRIDGE WILLIAM SIMS
Published: June 2004

Abstract: The following pages describe research grants awarded by the National Science Foundation that illustrate how different fields of science and technology can converge in order to increase human potential. Technological convergence involves the unification of the sciences of Nanotechnology, Biotechnology, Information Technology, and new technologies based on Cognitive Science (NBIC). Because it supports research across all major branches of science and technology, including the social and behavioral sciences, the NSF has been a focus of discussions about converging technologies to enhance human capabilities and serve human needs.
Pooling Problem: Alternate Formulations and Solution Methods
Authors: Audet Charles , Brimberg Jack , Hansen Pierre , Digabel Sébastien Le , Mladenović Nenad
Published: June 2004

The pooling problem, which is fundamental to the petroleum industry, describes a situation in which products possessing different attribute qualities are mixed in a series of pools in such a way that the attribute qualities of the blended products of the end pools must satisfy given requirements. It is well known that the pooling problem can be modeled through bilinear and nonconvex quadratic programming. In this paper, we investigate how best to apply a new branch-and-cut quadratic programming algorithm to solve the pooling problem. To this effect, we consider two standard models: One is based primarily on flow variables, and the other relies on the proportion of flows entering pools. A hybrid of these two models is proposed for general pooling problems. Comparison of the computational properties of flow and proportion models is made on several problem instances taken from the literature. Moreover, a simple alternating procedure and a variable neighborhood search heuristic are developed to solve large instances and compared with the well-known method of successive linear programming. Solution of difficult test problems from the literature is substantially accelerated, and larger ones are solved exactly or approximately.
Tolerance Sensitivity and Optimality Bounds in Linear Programming
Authors: Wendell Richard E.
Published: June 2004

Traditional sensitivity analysis in linear programming usually focuses on variations of one coefficient or term at a time. The tolerance approach was proposed to provide a decision maker with an effective and easy-to-use method to summarize the effects of simultaneous and independent changes in selected parameters. In particular, for variations of the objective function coefficients, the approach gives a maximum-tolerance percentage within which selected coefficients may vary from their estimated values (within a priori limits) while still retaining the same optimal basic feasible solution. Although an optimal solution may cease being optimal for variations beyond the maximum-tolerance percentage, it may still be close to optimal. Herein we characterize the potential loss of optimality for variations beyond the maximum-tolerance percentage as a maximum-regret function. We consider theoretical properties of this function and propose a method to compute a relevant portion of it.
Do Scientists Pay to Be Scientists?
Authors: Stern Scott
Published: June 2004

This paper explores the relationship between wages and the scientific orientation of R&D organizations. Firms that adopt a science-oriented research approach (i.e., “science”) allow their researchers to pursue and publish an individual research agenda. The adoption of science may be associated with a “taste” for science on the part of researchers (a preference effect) and/or as a “ticket of admission” to gain earlier access to scientific discoveries with commercial application (a productivity effect). These two effects differ in their impact on wages. Whereas the preference effect contributes to a negative compensating differential, the productivity effect may result in rent sharing. However, because science may be adopted by firms employing higher-quality researchers, cross-sectional evaluations of wages and science may be biased by unobserved heterogeneity. To overcome this bias, this paper introduces a novel empirical approach. Specifically, prior to accepting a given job, many scientists receive multiple job offers, allowing for the calculation of the wage-science relationship and controlling for differences in salary levels offered to individual researchers. Using a dataset composed of multiple job offers to postdoctoral biologists, the results suggest a negative relationship between wages and science. These findings are robust to restricting the sample to nonacademic job offers, but the findings depend critically on the inclusion of researcher fixed effects. Conditional on perceived ability, scientists do indeed pay to be scientists.
Rescheduling for New Orders
Authors: Hall Nicholas G. , Potts Chris N.
Published: June 2004

This paper considers scheduling problems where a set of original jobs has already been scheduled to minimize some cost objective, when a new set of jobs arrives and creates a disruption. The decision maker needs to insert the new jobs into the existing schedule without excessively disrupting it. Two classes of models are considered. First, we minimize the scheduling cost of all the jobs, subject to a limit on the disruption caused to the original schedule, where this disruption is measured in various ways. In the second class, a total cost objective, which includes both the original cost measure and the cost of disruption, is minimized. For both classes and various costs based on classical scheduling objectives, and for almost all problems, we provide either an efficient algorithm or a proof that such an algorithm is unlikely to exist. We also show how to extend both classes of models to deal with multiple disruptions in the form of repeated arrivals of new jobs. Our work refocuses the extensive literature on scheduling problems towards issues of rescheduling, which are important because of the frequency with which disruptions occur in manufacturing practice.
Nonconvex Structures in Nonlinear Programming
Authors: Scholtes Stefan
Published: June 2004

Nonsmoothness and nonconvexity in optimization problems often arise because a combinatorial structure is imposed on smooth or convex data. The combinatorial aspect can be explicit, e.g., through the use of “max,” “min,” or “if” statements in a model; or implicit, as in the case of bilevel optimization, where the combinatorial structure arises from the possible choices of active constraints in the lower-level problem. In analyzing such problems, it is desirable to decouple the combinatorial aspect from the nonlinear aspect and deal with them separately. This paper suggests a problem formulation that explicitly decouples the two aspects. A suitable generalization of the traditional Lagrangian framework allows an extension of the popular sequential quadratic programming (SQP) methodology to such structurally nonconvex nonlinear programs. We show that the favorable local convergence properties of SQP are retained in this setting and illustrate the potential of the approach in the context of optimization problems with max-min constraints that arise, for example, in robust optimization.
Optimal Auctioning and Ordering in an Infinite Horizon Inventory-Pricing System
Authors: van Ryzin Garrett , Vulcano Gustavo
Published: June 2004

We consider a joint inventory-pricing problem in which buyers act strategically and bid for units of a firm's product over an infinite horizon. The number of bidders in each period as well as the individual bidders' valuations are random but stationary over time. There is a holding cost for inventory and a unit cost for ordering more stock from an outside supplier. Backordering is not allowed. The firm must decide how to conduct its auctions and how to replenish its stock over time to maximize its profits. We show that the optimal auction and replenishment policy for this problem is quite simple, consisting of running a standard first-price or second-price auction with a fixed reserve price in each period and following an order-up-to (basestock) policy for replenishing inventory at the end of each period. Moreover, the optimal basestock level can be easily computed. We then compare this optimal basestock, reserve-price-auction policy to a traditional basestock, list-price policy. We prove that in the limiting case of one buyer per period and in the limiting case of a large number of buyers per period and linear holding cost, list pricing is optimal. List pricing also becomes optimal as the holding cost tends to zero. Numerical comparisons confirm these theoretical results and show that auctions provide significant benefits when: (1) the number of buyers is moderate, (2) holding costs are high, or (3) there is high variability in the number of buyers per period.
From Persistence to Pursuit: A Longitudinal Examination of Momentum During the Early Stages of Strategic Change
Authors: Jansen Karen J.
Published: June 2004

This study moves beyond the dominant “strategic persistence” view of momentum toward one focused on the energy associated with pursuit of a change goal. A conceptual distinction is made between inertia, the momentum associated with strategic persistence, and the momentum of strategic change. Building on this distinction, a theoretical framework is developed that examines the influence of various change-related events and social processes on momentum during the early stages of organizational change. The research reported in this manuscript was conducted over a 10-month period in an organization attempting to change its culture, employing both qualitative and longitudinal quantitative methods. This study provides validity evidence for the proposed momentum construct and identifies various factors that predict momentum. Results support a spiraling relationship between momentum and goal attainment, such that momentum predicts progress toward goal attainment, which then influences subsequent momentum. Practical implications and directions for future research are provided based on these findings.
Ziprasidone, a New Atypical Antipsychotic Drug
Authors: Carnahan Ryan M. , Lund Brian C. , Perry Paul J.
Published: June 2004

Although the introduction of antipsychotic drugs in 1954 was a breakthrough in the treatment of patients with schizophrenia, these agents have a number of adverse effects that limit effectiveness and compliance. The atypical antipsychotic drugs provide an improved tolerability profile, particularly in minimizing extrapyramidal side effects; however, they are associated with significant weight gain, which may be related to growing evidence linking the atypical agents with diabetes and hyperlipidemia. Ziprasidone, a new atypical antipsychotic drug, was demonstrated in clinical trials to be more efficacious than placebo and similar in efficacy to haloperidol in the treatment of schizophrenia. Like the existing atypical agents, ziprasidone has a rate of extrapyramidal side effects similar to that of placebo and does not cause significant elevations in prolactin levels. In contrast, ziprasidone has a low propensity for causing weight gain. For patients requiring an antipsychotic drug, ziprasidone represents a new treatment option with a limited adverse effect profile.
Simvastatin‐Associated Memory Loss
Authors: Orsi Amanda , Sherman Olga , Woldeselassie Zegga
Published: June 2004

The statins are widely used to treat dyslipidemias. They are generally associated with mild adverse effects, but rarely, more serious reactions may occur. A 51‐year‐old man experienced delayed‐onset, progressive memory loss while receiving simvastatin for hypercholesterolemia. His therapy was switched to pravastatin, and memory loss resolved gradually over the next month, with no recurrence of the adverse effect.
From Dialysis Outcomes Quality Initiative to Kidney Disease Outcomes Quality Initiative: New Clinical Practice Guidelines in Nephrology—What the Practicing Pharmacist Needs to Know
Authors: Bailie George R.
Published: June 2004

The use of clinical practice guidelines (CPGs) to guide rational treatment of patients is hardly novel to most areas of medicine or pharmacy but is a relatively new concept in nephrology where practice patterns have been dictated predominantly by opinion. This situation has undergone significant and dramatic change in the last few years, however, and CPGs have now been produced to address the management problems that face clinicians caring for patients with kidney diseases. This is the first of a series of planned articles designed to review these new kidney‐related CPGs that are most likely to affect the practice of pharmacy in many areas. This article provides a broad overview to the background of the development of CPGs in nephrology and the methodology used. Subsequent articles will identify in some detail current and pending CPGs that relate to pharmacotherapy.
Inhibition of Streptokinase‐Induced, Antibody‐Mediated Platelet Aggregation with Tirofiban After Exposure to Streptokinase or Streptococcal Infection
Authors: Courval Maryse , Palisaitis Donald A. , Diodati Jean G. , Lesperance Bernard , Pharand Chantal
Published: June 2004

Study Objective. To evaluate the effect of tirofiban (a glycoprotein IIb‐IIIa inhibitor) in preventing streptokinase‐induced, antibody‐mediated platelet aggregation after administration of streptokinase or development of a streptococcal infection.

Design. Prospective analysis.

Setting. Research center of a Canadian hospital.

Participants. Forty‐five healthy volunteers, 45 patients who had received streptokinase within the past 3 years, and 13 patients who had a severe streptococcal infection also within the past 3 years.

Intervention. Blood samples were drawn to measure the extent of inhibition of streptokinase‐induced, antibody‐mediated platelet activation and aggregation by tirofiban.

Measurements and Main Results. Platelet aggregation was measured by using a turbidimetric method. The extent of inhibition by tirofiban was measured by incubating tirofiban for 2 minutes before adding streptokinase 5000 U/ml. Also, tirofiban was added 2 minutes before adding adenosine 5′‐diphosphate (ADP) 2 μM/L into the last tube as a comparison. Streptokinase‐induced, antibody‐mediated platelet aggregation was observed in 10 (22%) of the 45 patients treated with streptokinase, in 3 (23%) of the 13 patients with streptococcal infection, and in none of the 45 healthy volunteers. Tirofiban inhibited streptokinase‐induced, antibody‐mediated platelet aggregation by 89 ± 14% (p<0.001). Similarly, ADP‐induced platelet aggregation was inhibited by 92 ± 6% (p<0.001) with tirofiban.

Conclusion. Streptokinase‐induced, antibody‐mediated platelet aggregation occurred in 13 (22%) of 58 patients who received streptokinase or were exposed to a streptococcal infection in the past 3 years. Such patients may not benefit from streptokinase therapy. In these patients, tirofiban significantly decreased the extent of antistreptokinase antibody–mediated platelet aggregation. Hence, patients undergoing streptokinase therapy may benefit from tirofiban as adjunctive therapy.
Tobramycin Pharmacokinetics in Children with Febrile Neutropenia Undergoing Stem Cell Transplantation: Once‐Daily versus Thrice‐Daily Administration
Authors: Dupuis L. Lee , Sung Lillian , Taylor Tracey , Abdolell Mohamed , Allen Upton , Doyle John , Taddio Anna
Published: June 2004

Study Objectives. To describe the pharmacokinetic disposition of tobramycin in children undergoing stem cell transplantation (SCT) after intravenous administration either every 24 hours or every 8 hours, and to use this information to create initial dosing guidelines for administration every 24 hours in this patient population.

Design. Pharmacokinetic analysis of a randomized controlled trial.

Setting. The Hospital for Sick Children, Toronto, Ontario, Canada.

Patients. Sixty children (< 18 yrs) with febrile neutropenia undergoing stem cell transplantation.

Intervention. Patients were randomized to receive intravenous tobramycin either every 24 hours (29 patients) or every 8 hours (31 patients). Initially, they received either 2.5 mg/kg/dose every 8 hours or weight‐based doses by age group (< 5 yrs, 9 mg/kg/dose; 5 to < 12 yrs, 8 mg/kg/dose; ≥ 12 yrs, 7 mg/kg/dose) every 24 hours.

Measurements and Main Results. Serum tobramycin concentrations were obtained at 2 and 8 hours after the first dose. Initial guidelines for dosing every 24 hours were derived using the parameters from all patients to achieve a maximum serum concentration (Cmax) of 20–22.5 mg/L and a drug‐free interval (time during dosing interval when the tobramycin concentration was < 1 mg/L) of at least 4 hours. After the first tobramycin dose, the elimination rate constant (kel) and volume of distribution (Vd) observed in the every‐8‐hour group (23 patients) were 0.34 ± 0.09 hours−1 and 0.48 ± 0.21 L/kg, respectively. The kel and Vd in the every‐24‐hour group (22 patients) were 0.43 ± 0.12 hr−1 and 0.43 ± 0.26 L/kg, respectively. Tobramycin Vd varied with age. Initial doses of tobramycin every 24 hours recommended to achieve the target parameters are 10 mg/kg/dose for patients aged 6 months to less than 9 years, 8 mg/kg/dose for those aged 9 to less than 12 years, and 6 mg/kg/dose for those aged 12 years or older.

Conclusion. Children undergoing SCT who receive tobramycin every 24 hours should receive an initial dose based on age. Further validation of the proposed dosing guidelines is required.
Statins and Liver Toxicity: A Meta‐Analysis
Authors: de Denus Simon , Spinler Sarah A. , Miller Kristin , Peterson Andrew M.
Published: June 2004

Study Objective. To assess the risk of liver function test (LFT) abnormalities with the use of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) for the treatment of hyperlipidemia.

Design. Meta‐analysis of randomized, placebo‐controlled trials of statins used for the treatment of hyperlipidemia or for primary or secondary prevention of cardiovascular disease.

Setting. University research center.

Patients. A total of 49,275 patients from 13 trials.

Intervention. A literature search of published clinical trials was performed in MEDLINE (January 1966–March 2003) and the Cochrane Controlled Trials Registry (first quarter 2003). Studies also were identified from the references of the trials and of published systematic reviews.

Measurements and Main Results. For a trial to be included in the meta‐analysis, its duration of follow‐up had to be at least 48 weeks and the trial had to include at least 400 patients, with at least 200 treated with a statin. Trials conducted in transplant recipients were excluded. The proportion of patients having LFT abnormalities was low in both groups (statins 1.14% vs placebo 1.05%, odds ratio [OR] 1.26, 95% confidence interval [CI] 0.99–1.62, p=0.07). Only fluvastatin was associated with a significant increase in the odds of having LFT abnormalities (fluvastatin 1.13% vs placebo 0.29%, OR 3.54, 95% CI 1.1–11.6, p=0.04) compared with placebo, although this finding was based on only two trials.

Conclusions. Our results support previous observations that pravastatin, lovastatin, and simvastatin at low‐to‐moderate doses are not associated with a significant risk of LFT abnormalities. Additional data are required to determine whether other statins have a similar safety profile.
Sulfonylurea Treatment of Type 2 Diabetes Mellitus: Focus on Glimepiride
Authors: Korytkowski Mary T.
Published: June 2004

Sulfonylureas, which have evolved through two generations since their introduction nearly 50 years ago, remain the most frequently prescribed oral agents for treatment of patients with type 2 diabetes mellitus. Glyburide, glipizide, and glimepiride, the newest sulfonylureas, are as effective at lowering plasma glucose concentrations as first‐generation agents but are more potent, better tolerated, and associated with a lower risk of adverse effects. Differences in their binding affinity to the β‐cell sulfonylurea receptor have been described, with preservation of cardioprotective responses to ischemia with glimepiride. Clinical studies have shown glimepiride to be safe and effective in reducing fasting and postprandial glucose levels, as well as glycosylated hemoglobin concentrations, with dosages of 1–8 mg/day. In comparative trials, glimepiride was as effective in lowering glucose levels as glyburide and glipizide, but glimepiride was associated with a reduced likelihood of hypoglycemia and a smaller increase in fasting insulin and C‐peptide levels than glyburide, and a more rapid lowering of fasting plasma glucose levels than glipizide. Glimepiride also improves first‐phase insulin secretion, which plays an important role in reducing postprandial hyperglycemia. Insulin secretagogues, specifically glimepiride, merit consideration as first‐line therapy for patients with type 2 diabetes.
Migraine Headache Misconceptions: Barriers to Effective Care
Authors: Wenzel Richard , Dortch Marcus , Cady Roger , Lofland Jennifer H. , Diamond Seymour
Published: June 2004

Migraine headaches affect 12% of the adult population in the United States and cause a significant economic loss due to decreased workplace productivity. Although interactions between pharmacists and individuals with headache are common, few pharmacists receive adequate training regarding migraine therapy. We refute several misconceptions that hinder effective care, such as that migraine is a vascular disease, triptans cause rampant cardiac‐related morbidity and even mortality, a best oral triptan exists, sinus and tension headaches are prevalent, and migraine is a minor economic problem. Our pathophysiologic understanding demonstrates that migraine is a neurologic process of the trigeminovascular system, of which vascular effects are secondary. This process can result in a myriad of clinical signs and symptoms, often leading to a misdiagnosis of sinus or tension headache. The last decade's experience with triptans in more than half a billion people worldwide reveals a benign adverse‐effect profile, particularly when taken early in an attack. Published reports and real‐world experiences illustrate that these drugs do not merit fears of triptan‐induced cardiac consequences in appropriately selected individuals. Society's productivity loss due to migraine is measured in billions of dollars. Restoring a patient's ability to function normally is now recognized as the primary treatment goal, not merely relieving pain. Thus, the overreliance on “pain killer” drugs such as butalbital‐containing products and the continued underutilization of migraine‐specific drugs need to be addressed. Opportunities exist for pharmacists and other health care providers to dispel continually propagated migraine misconceptions and familiarize themselves with advances in therapy. Such actions will benefit patients, the health care system, and society as a whole.