bluuebunny/crossref_metadata_2025 huggingface dataset:
Polo-like kinase confers MPF autoamplification competence to growingXenopusoocytes
Authors: Karaiskou Anthi , Leprêtre Anne-Claire , Pahlavan Golbahar , Du Pasquier David , Ozon René , Jessus Catherine
Published: March 2004

During oogenesis, the Xenopus oocyte is blocked in prophase of meiosis I. It becomes competent to resume meiosis in response to progesterone at the end of its growing period (stage VI of oogenesis). Stage IV oocytes contain a store of inactive pre-MPF (Tyr15-phosphorylated Cdc2 bound to cyclin B2); the Cdc25 phosphatase that catalyzes Tyr15 dephosphorylation of Cdc2 is also present. However, the positive feedback loop that allows MPF autoamplification is not functional at this stage of oocyte growth. We report that when cyclin B is overexpressed in stage IV oocytes, MPF autoamplification does not occur and the newly formed cyclin B-Cdc2 complexes are inactivated by Tyr15 phosphorylation, indicating that Myt1 kinase remains active and that Cdc25 is prevented to be activated. Plx1 kinase (or polo-like kinase), which is required for Cdc25 activation and MPF autoamplification in full grown oocytes is not expressed at the protein level in small stage IV oocytes. In order to determine if Plx1 could be the missing regulator that prevents MPF autoamplification, polo kinase was overexpressed in stage IV oocytes. Under these conditions, the MPF-positive feedback loop was restored. Moreover, we show that acquisition of autoamplification competence does not require the Mos/MAPK pathway.
Depolarization-induced translocation of the RNA-binding protein Sam68 to the dendrites of hippocampal neurons
Authors: Fredj Naïla Ben , Grange Julien , Sadoul Rémy , Richard Stéphane , Goldberg Yves , Boyer Véronique
Published: March 2004

The traffic and expression of mRNAs in neurons are modulated by changes in neuronal activity. The regulation of neuronal RNA-binding proteins is therefore currently receiving attention. Sam68 is a ubiquitous nuclear RNA-binding protein implicated in post-transcriptional processes such as signal-dependent splice site selection. We show that Sam68 undergoes activity-responsive translocation to the soma and dendrites of hippocampal neurons in primary culture. In unstimulated neurons transiently expressing a GFP-Sam68 fusion protein, 90% of the cells accumulated the protein exclusively in the nucleus, and 4% showed extension of GFP-Sam68 to the dendrites. This nuclear expression pattern required the integrity of the Sam68 N-terminus. When present, the dendritic GFP-Sam68 formed granules, 26% of which were colocalized with ethidium bromide-stained RNA clusters. Most of the GFP-Sam68 granules were completely stationary, but a few moved in either a retrograde or anterograde direction. Following depolarization by 25 mM KCl, 50% of neurons displayed dendritic GFP-Sam68. GFP-Sam68 invaded the dendrites after 2 hours with high KCl, and returned to the nucleus within 3 hours after termination of the KCl treatment. A control GFP fusion derived from the SC-35 splicing factor remained fully nuclear during depolarization. No significant change was observed in the phosphorylation of Sam68 after depolarization. Translocation of Sam68 to the distal dendrites was microtubule dependent. Blockade of calcium channels with nimodipine abolished the translocation. Furthermore, inhibition of CRM-1-mediated nuclear export by leptomycin B partially prevented the depolarization-induced nuclear efflux of GFP-Sam68. These results support the possible involvement of Sam68 in the activity-dependent regulation of dendritic mRNAs.
Increased phosphorylation of AKAP by inhibition of phosphatidylinositol 3-kinase enhances human sperm motility through tail recruitment of protein kinase A
Authors: Luconi Michaela , Carloni Vinicio , Marra Fabio , Ferruzzi Pietro , Forti Gianni , Baldi Elisabetta
Published: March 2004

Sperm motility is regulated by a complex balance between kinases and phosphatases. Among them, phosphatidylinositol 3-kinase (PI 3-kinase) has been recently suggested to negatively regulate sperm motility (Luconi, M., Marra, F., Gandini, L., Lenzi, A., Filimberti, E., Forti, G. and Baldi, E. (2001). Hum. Reprod. 16, 1931-1937). We demonstrate the presence and activity of PI 3-kinase in human spermatozoa and have investigated the molecular mechanism(s) by which the PI 3-kinase inhibitor, LY294002, triggers an increase in sperm motility. PI 3-kinase inhibition results in an increase in intracellular cAMP levels and in tyrosine phosphorylation of the protein kinase A-anchoring protein AKAP3. These effects finally result in a stimulation of protein kinase A (PKA) binding to AKAP3 in sperm tails through the regulatory subunit RIIβ. The increased binding of RIIβ to AKAP3 induced by LY294002 is mainly due to tyrosine phosphorylation of AKAP3, since it is completely blocked by the tyrosine kinase inhibitor erbstatin, which also reverses the effects of LY294002 on motility and suppresses PKA-AKAP3 interaction. The requirement of PKA binding to AKAP3 for sperm motility is confirmed by the reduction of motility induced by an inhibitor of RIIβ-AKAP3 binding, Ht31, whose effects on sperm motility and PKA binding to AKAP3 are reversed by LY294002.

These results demonstrate that PI 3-kinase negatively regulates sperm motility by interfering with AKAP3-PKA binding, providing the first evidence of a molecular mechanism by which PKA can be targeted to sperm tails by interaction with tyrosine phosphorylated form of AKAP3.
Nuclear location of a chromatin insulator inDrosophila melanogaster
Authors: Xu Qinghao , Li Mo , Adams Jessica , Cai Haini N.
Published: March 2004

Chromatin-related functions are associated with spatial organization in the nucleus. We have investigated the relationship between the enhancer-blocking activity and subnuclear localization of the Drosophila melanogaster suHw insulator. Using fluorescent in situ hybridization, we observed that genomic loci containing the gypsy retrotransposon were distributed closer to the nuclear periphery than regions without the gypsy retrotransposon. However, transgenes containing a functional 340 bp suHw insulator did not exhibit such biased distribution towards the nuclear periphery, which suggests that the suHw insulator sequence is not responsible for the peripheral localization of the gypsy retrotransposon. Antibody stains showed that the two proteins essential for the suHw insulator activity, SUHW and MOD(MDG4), are not restricted to the nuclear periphery. The enhancer-blocking activity of suHw remained intact under the heat shock conditions, which was shown to disrupt the association of gypsy, SUHW and MOD(MDG4) with the nuclear periphery. Our results indicate that the suHw insulator can function in the nuclear interior, possibly through local interactions with chromatin components or other nuclear structures.
A new structural element containing glycine-rich proteins and rhamnogalacturonan I in the protoxylem of seed plants
Authors: Ryser Ulrich , Schorderet Martine , Guyot Romain , Keller Beat
Published: March 2004

The water pipes of elongating plant organs are the result of programmed cell death and are formed by the walls of dead and empty protoxylem elements. These protoxylem elements are passively elongated many times by the surrounding tissue before they are replaced and collapse. Well-known adaptations for this unique task include the characteristic secondary wall thickenings, forming rings and helices. A new, clearly distinct structural element containing glycine-rich proteins is now visualized for the first time, using confocal laser scanning microscopy in the mature protoxylem of elongating organs of seed plants. This structural element is arranged along the longitudinal axis of the protoxylem elements. It interconnects the secondary wall thickenings within and between protoxylem elements, as well as the protoxylem with other cell types such as xylem parenchyma cells and metaxylem elements. The structural element is stable against detergent extractions, proteinase, pectinase and cellulase hydrolysis, and is closely associated with rhamnogalacturonan-I, a pectic polysaccharide. The results clearly demonstrate that the cell wall of protoxylem cells is a highly dynamic and complex structure. The typical polysaccharide-rich primary wall of living and elongating plant cells is progressively modified and finally replaced by a protein-rich wall in the dead and passively stretched protoxylem elements. These glycine-rich walls originated early in the evolution of the seed plants as confirmed by the analysis of genomic information.
Dynamic recruitment of the adaptor protein LAT: LAT exists in two distinct intracellular pools and controls its own recruitment
Authors: Bonello Grégory , Blanchard Nicolas , Montoya Maria C. , Aguado Enrique , Langlet Claire , He Hai-Tao , Nunez-Cruz Selena , Malissen Marie , Sanchez-Madrid Francisco , Olive Daniel , Hivroz Claire , Collette Yves
Published: March 2004

The integral membrane adaptor protein linker for activation of T cells (LAT) couples the T-cell receptor (TCR) with downstream signalling and is essential for T-cell development and activation. Here, we investigate the dynamic distribution of LAT-GFP fusion proteins by time-lapse video imaging of live T lymphocytes interacting with antigen-presenting cells. We show that LAT forms two distinct cellular pools, one at the plasma membrane and one that co-distributes with transferrin-labelled intracellular compartments also containing the TCR/CD3-associated ζ chain. The distribution of LAT between these two pools is dependent on LAT intracytoplasmic residues. Whereas plasma membrane-associated LAT is recruited to immune synapses after a few seconds of cell conjugate formation, the intracellular pool is first polarized and then recruited after a few minutes. We further show that LAT intracytoplasmic amino acid residues, particularly the Tyr136, 175, 195 and 235 residues, are required for its own recruitment to the immune synapse and that a herein-identified juxtamembrane LAT region (amino acids 32-104) is involved in the localization of LAT in intracellular pools and in T-cell signalling. Altogether, our results demonstrate that LAT controls its own recruitment at the immune synapse, where it is required as a scaffold protein for the signalling machinery. The results also suggest that the intracellular pool of LAT might be required for T-cell activation.
Disruption of spermatogenesis in mice lacking A-type lamins
Authors: Alsheimer Manfred , Liebe Bodo , Sewell Lori , Stewart Colin L. , Scherthan Harry , Benavente Ricardo
Published: March 2004

Nuclear lamins are structural protein components of the nuclear envelope. Mutations in LMNA, the gene coding for A-type lamins, result in several human hereditary diseases, the laminopathies, which include Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy and Hutchinson-Gilford progeria. Similar to the human conditions, it has been shown that Lmna–/– mice develop severe dystrophies of muscle and fat tissues. Here we report that Lmna–/– mice display impaired spermatogenesis, with a significant accumulation of spermatocytes I during early prophase I stages, while pachytene spermatocytes are severely defective in synaptic pairing of the sex chromosomes in particular, leading to massive apoptosis during the pachytene stage of meiosis I. In contrast, oogenesis remains largely unaffected in Lmna–/– mice. These results reveal A-type lamins as important determinants of male fertility.
Chromatin loops are selectively anchored using scaffold/matrix-attachment regions
Authors: Heng Henry H. Q. , Goetze Sandra , Ye Christine J. , Liu Guo , Stevens Joshua B. , Bremer Steven W. , Wykes Susan M. , Bode Juergen , Krawetz Stephen A.
Published: March 2004

The biological significance of nuclear scaffold/matrix-attachment regions (S/MARs) remains a topic of long-standing interest. The key to understanding S/MAR behavior relies on determining the physical attributes of in vivo S/MARs and whether they serve as rigid or flexible chromatin loop anchors. To analyze S/MAR behavior, single and multiple copies of the S/MAR-containing constructs were introduced into various host genomes of transgenic mice and transfected cell lines. These in vivo integration events provided a system to study the association and integration patterns of each introduced S/MAR. By utilizing FISH to visualize directly the localization of S/MARs on the nuclear matrix or chromatin loop, we were able to assign specific attributes to the S/MAR. Surprisingly, when multiple-copy S/MARs were introduced they were selected and used as nuclear matrix anchors in a discriminatory manner, even though they all contained identical primary sequences. This selection process was probably mediated by S/MAR availability including binding strength and copy number, as reflected by the expression profiles and association of multi-copy tandem inserted constructs. Whereas S/MARs functioned as the mediators of loop attachment, they were used in a selective and dynamic fashion. Consequently, S/MAR anchors were necessary but not sufficient for chromatin loops to form. These observations reconcile many seemingly contradictory attributes previously associated with S/MARs.
Functional compatibility between isoform α and β of type II DNA topoisomerase
Authors: Sakaguchi Ayako , Kikuchi Akihiko
Published: March 2004

DNA topoisomerase II (topo II) plays a crucial role in controlling the conformation of both DNA and whole chromosomes. This activity is essential for several cellular events such as DNA replication, transcription, chromosome condensation and segregation. In mammals, two genes code for isoforms of topo II, termed α and β. They are similar in primary structure and have almost identical catalytic properties in vitro. We transfected HeLa cells with small interfering RNAs (siRNAs) targeted against either topo IIα or IIβ, and succeeded in knocking down the expression of the corresponding protein. Chromosomes were condensed and aligned at metaphase in topo IIα-knockdown cells. Although some lagging chromosomes were observed, they were still segregated at anaphase despite the absence of topo IIα. When both topo IIα and topo IIγ were removed, the segregation of chromosomes was severely arrested, suggesting that topo IIγ could partially substitute for topo IIα. Double-knockdown experiments also revealed that topo II was required for shortening of the chromosome axis.
Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology
Authors: Stojanovski Diana , Koutsopoulos Olga S. , Okamoto Koji , Ryan Michael T.
Published: March 2004

Mitochondria undergo balanced fission and fusion events that enable their appropriate networking within the cell. In yeast, three factors have been identified that co-ordinate fission events at the mitochondrial outer membrane. Fis1p acts as the outer membrane receptor for recruitment of the dynamin member, Dnm1p and the WD40-repeat-containing protein Mdv1p. In mammals, the Dnm1p counterpart Drp1 has been characterized, but other components have not. Here, we report the characterization of human Fis1 (hFis1). hFis1 is inserted into the mitochondrial outer membrane via a C-terminal transmembrane domain that, along with a short basic segment, is essential for its targeting. Although expression of hFis1 does not complement the phenotype of yeast cells lacking Fis1p, overexpression of hFis1 in tissue culture cells nevertheless causes mitochondrial fragmentation and aggregation. This aggregation could be suppressed by expressing a dominant-negative Drp1 mutant (Drp1K38A). Knockdown of hFis1 in COS-7 cells using RNA interference results in mitochondrial morphology defects with notable extensions in the length of mitochondrial tubules. These results indicate that the levels of hFis1 at the mitochondrial surface influences mitochondrial fission events and hence overall mitochondrial morphology within the cell.
Proteins that bind A-type lamins: integrating isolated clues
Authors: Zastrow Michael S. , Vlcek Sylvia , Wilson Katherine L.
Published: March 2004

What do such diverse molecules as DNA, actin, retinoblastoma protein and protein kinase Cα all have in common? They and additional partners bind `A-type' lamins, which form stable filaments in animal cell nuclei. Mutations in A-type lamins cause a bewildering range of tissue-specific diseases, termed `laminopathies', including Emery-Dreifuss muscular dystrophy and the devastating Hutchinson-Gilford progeria syndrome, which mimics premature aging. Considered individually and collectively, partners for A-type lamins form four loose groups: architectural partners, chromatin partners, gene-regulatory partners and signaling partners. We describe 16 partners in detail, summarize their binding sites in A-type lamins, and sketch portraits of ternary complexes and functional pathways that might depend on lamins in vivo. On the basis of our limited current knowledge, we propose lamin-associated complexes with multiple components relevant to nuclear structure (e.g. emerin, nesprin 1α, actin) or signaling and gene regulation (e.g. LAP2α, retinoblastoma, E2F-DP heterodimers, genes) as `food for thought'. Testing these ideas will deepen our understanding of nuclear function and human disease.
Systematic approach to the planning and execution of product remanufacture
Authors: Parkinson H J , Thompson G
Published: March 2004

The challenge of remanufacturing is the production of quality products from returned discarded cores of unknown quality. Case studies and published literature reveal that there are no established processes tailored to the particular needs of product remanufacture. This paper outlines the difficulties associated with the planning and execution of product remanufacture. It then presents a systematic approach for the planning and execution of product remanufacture based upon the failure mode and effect analysis (FMEA) method. The approach is demonstrated in case studies of the remanufacture of an air-conditioning unit and a turbocharger. The results from the case studies are discussed and conclusions are drawn. The wider issues associated with remanufacturing including reliability and safety, further research opportunities and the design of functional products are then discussed and conclusions drawn.
Speed estimation and control in a belt-driven system for a web production process. Part 2: Control strategy
Authors: Makin E , Acarnley P
Published: March 2004

This paper addresses the problem of estimating and controlling the speed of a belt-driven casting drum in a web production process, where direct measurement of drum speed is infeasible. Techniques for estimating web tension and casting drum speed, using measured values of brake and drive torque demand and speed, are described and verified by application to a laboratory casting drum facility. The estimates of web tension and casting drum speed are incorporated in a new speed control strategy, which counteracts the effects of creep and slip between the drive belt and pulleys. Experimental results demonstrate much improved steady-state speed holding and transient speed response of the casting drum, in comparison with the performance of the original controller: the steady-state speed error with nominal (50 per cent) web tension is reduced from 0.8 to 0.1 per cent, while the peak transient speed error for a 25 per cent change in web tension reduces from 4 to 0.5 per cent.
Enhancement of the low-level components of milling vibration signals by stochastic resonance
Authors: Klamecki B E
Published: March 2004

The enhancement of vibration signals by the addition of a random signal component was investigated. Vibration measurements during end-milling were made using an accelerometer mounted on the workpiece. A large number of tests were run with varying spindle speed, table speed, axial depth of cut, radial depth of cut and tool condition. Vibration signal frequency spectra were dominated by the cutting edge passing frequency, and so individual cutting edge effects such as cutting edge chipping or differences in amount of edge wear could not be identified easily. Similarly, machine characteristics such as spindle runout were overshadowed in vibration spectra by the dominant cutting edge passing frequency. To enhance the low-level signal components, a signal analysis procedure was constructed in which random components were added to accelerometer signals, a threshold signal level set and frequency spectra calculated from signal components exceeding the threshold. Enhancement of spectra peaks associated with low-level signal components was demonstrated. The effects of measurement system threshold level and added noise level on signal enhancement were determined.
A study of fouling and its effects on the performance of counter flow wet cooling towers
Authors: Khan J-U-R , Zubair S M
Published: March 2004

Fouling of fills is one of the most important factors affecting cooling tower thermal performance, reducing the effectiveness and capability of the cooling tower. In this paper, experimental data on fill fouling that have been reported in the literature are used to develop a fouling model. The model predicts the decrease in the fill performance index, nF, with the growth of fouling on fill materials. The authenticity of the fouling model is validated by experimental data. The fouling model, in conjunction with a detailed model of a counterflow wet cooling tower, is used to study the effect of fouling on cooling tower effectiveness and water outlet temperature. The models are used for studying the performance of small and medium-sized cooling towers under different air inlet wet-bulb temperatures. The results demonstrate that fouling of fills negates any gains in cooling tower performance that result from decreasing values of air inlet wet-bulb temperature. Furthermore, it is demonstrated that this effect is more pronounced in medium-sized cooling towers compared with small towers. Water outlet temperature decreases by 23.5 per cent in the case of small cooling towers, compared with an 18.3 per cent decrease for medium-sized towers under similar operating conditions.
Using statistically designed experiments for safety system optimization
Authors: Andrews J D , Bartlett L M
Published: March 2004

This paper describes the method of statistically designed experiments (SDEs) which is used as a structured method to investigate the best setting for a number of decision variables in a system design problem. Traditionally, in the design of safety-critical systems, a trial and error type approach is undertaken to achieve a final system that meets the design objectives. This approach can be time consuming, and often only an adequate design is found rather than the optimal design for the available resources. Optimal use of resources should be imperative when possible lives are at risk. To demonstrate the pracaticality of this new structured approach for optimizing a safety system design, a high-integrity safety system has been used. Each design is analysed using the binary decision diagram analysis technique to establish the system unavailability, which is penalized if the system constraints are exceeded. System constraints indicate the limitations on the resources that can be utilized. The SDE approach highlights good and bad settings for possible design variables. This knowledge can then be used by more sophisticated search techniques. The latter part of this paper analyses the results from the best design generated using the SDE, for further optimization using localized optimization approaches.
Dehydration Polymerization in Aqueous Medium Catalyzed by Lipase
Authors: Kobayashi Shiro , Uyama Hiroshi , Suda Sakae , Namekawa Shuhei
Published: March 2004

Dehydration polymerization of a dicarboxylic acid and glycol proceeded in an aqueous medium by using lipase catalyst to produce an aliphatic polyester. Enzyme origin and the monomer structure affected the yield and molecular weight of the product polyester.
Multiperson Tournaments: An Experimental Examination
Authors: Orrison Alannah , Schotter Andrew , Weigelt Keith
Published: March 2004

Modern hierarchical organizations, like corporations, must motivate agents to work hard. Given their pyramid structure, it is not surprising that one commonly used motivator is the promotion tournament. In such tournaments, agents compete to advance to positions at higher organizational levels. Though these tournaments are common, little research has empirically looked at the interface of organizational structure and tournament design. This paper aims to take a step in filling this void by comparing the performance of various tournament designs using controlled laboratory techniques.
Ordering and Inventory Policies for Step Changes in the Unit Item Cost: A Discounted Cash Flow Approach
Authors: Grubbström Robert W. , Kingsman Brian G.
Published: March 2004

This paper considers the problem of determining the optimal ordering quantities of a purchased item where there are step changes in price, either up or down. Other costs incurred include ordering costs associated with each replenishment and holding costs related to capital tied up in inventory and physical stock holding. The net present value (NPV) principle is applied. Explicit expressions for the development of the optimal order quantities over time are presented. It is shown that three cases may be distinguished: (i) when the price change is very small, (ii) when an essential price increase occurs, and (iii) when there is an essential price decrease. Although the optimal last-order quantity before a price increase is similar in magnitude to what has been presented in other articles applying average cost approaches, in certain respects, this paper offers novel results contradictory to those suggested by other authors. Analysis shows that the average-cost model solutions are first-order approximations in the discount rate. Numerical evaluations of a range of price increases and times to the price increase suggest that, with certain important caveats, the average-cost formulae are likely to be acceptable for most practical situations for the infinite horizon situation.
Collaborative Prototyping and the Pricing of Custom-Designed Products
Authors: Terwiesch Christian , Loch Christoph H.
Published: March 2004

A major challenge in the creation of custom-designed products lies in the elicitation of customer needs. As customers are frequently unable to accurately articulate their needs, designers typically create one or several prototypes, which they then present to the customer. This process, which we call collaborative prototyping, allows both parties to anticipate the outcome of the design process. Prototypes have two advantages: They help the customer to evaluate the unknown customized product, and they guide both parties in the search for the ideal product specification. Collaborative prototyping involves two economic agents, with different information structures and different—and potentially conflicting—objective functions. This raises several interesting questions: how many prototypes should be built, who should pay for them, and how should they and the customized product be priced. We show that, depending on the design problem and the market characteristics, the designer should offer prototypes at a profit, at cost, or even for free.
50th Anniversary Article: Technological Innovation, Product Development, and Entrepreneurship in Management Science
Authors: Shane Scott A. , Ulrich Karl T.
Published: March 2004

This article is a review of work published in Management Science on the topics of technological innovation, product development, and entrepreneurship since the inception of the journal in 1954. We intend the article to serve two goals. First, we hope that it will be useful to doctoral students and researchers interested in understanding what questions have been addressed in Management Science in the area of innovation. Second, we hope that the article will be useful to sociologists of science who are interested in understanding how knowledge develops in a field. We organize the literature into 12 themes. We then describe some aggregate properties of the articles. In an online supplement, we present brief summaries of the 250 articles we have identified as falling in the domain of our department.
An Efficient Algorithm for Real-Time Estimation and Prediction of Dynamic OD Tables
Authors: Bierlaire M. , Crittin F.
Published: March 2004

The problem of estimating and predicting Origin-Destination (OD) tables is known to be important and difficult. In the specific context of Intelligent Transportation Systems (ITS), the dynamic nature of the problem and the real-time requirements make it even more intricate.

We consider here a least-square modeling approach for solving the OD estimation and prediction problem, which seems to offer convenient and flexible algorithms. The dynamic nature of the problem is represented by an autoregressive process, capturing the serial correlations of the state variables. Our formulation is inspired from Cascetta et al. (1993) and Ashok and Ben-Akiva (1993). We compare the Kalman filter algorithm to LSQR, an iterative algorithm proposed by Paige and Saunders (1982) for the solution of large-scale least-squares problems. LSQR explicitly exploits matrix sparsity, allowing to consider larger problems likely to occur in real applications.

We show that the LSQR algorithm significantly decreases the computation effort needed by the Kalman filter approach for large-scale problems. We also provide a theoretical number of flops for both algorithms to predict which algorithm will perform better on a specific instance of the problem.
A Simulation Model for Predicting Yacht Match Race Outcomes
Authors: Philpott A. B. , Henderson S. G. , Teirney D.
Published: March 2004

We outline the development of a model for predicting the outcome of a yacht match race between two competing designs. The model is a fixed-time-increment simulation that accounts for the dynamic performance of each yacht. The wind speed and direction are modelled using hidden Markov chain models. Each yacht is assumed to follow a fixed sailing strategy determined by a set of simple decision rules. The simulation models both yachts simultaneously and accounts for interactions between them—for example, when they cross. The model is illustrated by applying it to International America's Cup Class designs.
Infinite Horizon Production Scheduling in Time-Varying Systems Under Stochastic Demand
Authors: Cheevaprawatdomrong Torpong , Smith Robert L.
Published: March 2004

We consider infinite horizon production scheduling under stochastic demand. All problem data are allowed to vary across periods, including demand distributions, costs, and revenues. A forecast horizon, when it exists, is a finite problem horizon with the property that the corresponding first-period optimal production decision remains optimal regardless of demand and cost projections beyond this horizon. Thus, a forecast horizon allows us to reduce the amount of future data we need to forecast to solve for an optimal first decision for the infinite horizon problem. In this paper, we establish the existence of a forecast horizon under the assumptions that (1) costs and revenues are time-varying linear, and (2) demand is never eventually zero. A key result for establishing the existence and computation of forecast horizons is the monotonicity, and hence convergence, of optimal first-period policies as the horizon increases of finite horizon versions of the infinite horizon problem. A closed-form formula is provided for computing a forecast horizon that depends only on the discount factor and uniform upper and lower bounds on demand and unit production and inventory holding costs. In particular, its value is independent of, and determined in advance of, forecasting the demand distribution. We show that the effect of uncertainty in demand is to increase the forecast horizon associated with a deterministic problem by a constant plus a factor equal to one plus the ratio of these upper to lower bounds on per-period demand. The associated forecast horizon can be surprisingly short, even a few days, when the inventory costs are high.
Dimensioning Large Call Centers
Authors: Borst Sem , Mandelbaum Avi , Reiman Martin I.
Published: March 2004

We develop a framework for asymptotic optimization of a queueing system. The motivation is the staffing problem of large call centers, which we have modeled as M/M/N queues with N, the number of agents, being large. Within our framework, we determine the asymptotically optimal staffing level N* that trades off agents' costs with service quality: the higher the latter, the more expensive is the former. As an alternative to this optimization, we also develop a constraint satisfaction approach where one chooses the least N* that adheres to a given constraint on waiting cost. Either way, the analysis gives rise to three regimes of operation: quality-driven, where the focus is on service quality; efficiency-driven, which emphasizes agents' costs; and a rationalized regime that balances, and in fact unifies, the other two. Numerical experiments reveal remarkable accuracy of our asymptotic approximations: over a wide range of parameters, from the very small to the extremely large, N* is exactly optimal, or it is accurate to within a single agent. We demonstrate the utility of our approach by revisiting the square-root safety staffing principle, which is a long-existing rule of thumb for staffing the M/M/N queue. In its simplest form, our rule is as follows: if c is the hourly cost of an agent, and a is the hourly cost of customers' delay, then N* = R + y* (a/c)√R, where R is the offered load, and y*(·) is a function that is easily computable.
Coffee, Tea, or …?: A Markov Decision Process Model for Airline Meal Provisioning
Authors: Goto Jason H. , Lewis Mark E. , Puterman Martin L.
Published: March 2004

This paper develops and analyzes a finite horizon Markov decision process model for the airline meal provisioning activity focusing explicitly on developing policies for determining and revising the number of meals to upload. Using one year of daily data from over 40 flights, the paper shows that the optimal policies can result in both improved customer service and significant dollar savings, especially in long haul flights. It also applies the model to derive an efficient frontier and investigate tradeoffs between having too few and too many meals on a flight.
Airline Schedule Planning: Integrated Models and Algorithms for Schedule Design and Fleet Assignment
Authors: Lohatepanont Manoj , Barnhart Cynthia
Published: March 2004

Constructing a profitable schedule is of utmost importance to an airline because its profitability is critically influenced by its flight offerings. We focus our attention on the steps of the airline schedule planning process involving schedule design and fleet assignment. Airline schedule design involves determining when and where to offer flights such that profits are maximized, and fleet assignment involves assigning aircraft types to flight legs to maximize revenue and minimize operating cost. We present integrated models and solution algorithms that simultaneously optimize the selection of flight legs for and the assignment of aircraft types to the selected flight legs. Preliminary results, based on data from a major U.S. airline, suggest that significant benefits can be achieved.
The Heterogeneous Vehicle-Routing Game
Authors: Engevall Stefan , Göthe-Lundgren Maud , Värbrand Peter
Published: March 2004

In this paper, we study a cost-allocation problem that arises in a distribution-planning situation at the Logistics Department at Norsk Hydro Olje AB, Stockholm, Sweden. We consider the routes from one depot during one day. The total distribution cost for these routes is to be divided among the customers that are visited. This cost-allocation problem is formulated as a vehicle-routing game (VRG), allowing the use of vehicles with different capacities. Cost-allocation methods based on different concepts from cooperative game theory, such as the core and the nucleolus, are discussed. A procedure that can be used to investigate whether the core is empty or not is presented, as well as a procedure to compute the nucleolus. Computational results for the Norsk Hydro case are presented and discussed.
Allocation of Railway Rolling Stock for Passenger Trains
Authors: Abbink Erwin , van den Berg Bianca , Kroon Leo , Salomon Marc
Published: March 2004

For a commercially operating railway company, providing a high level of service for the passengers is of utmost importance. The latter requires high punctuality of the trains and an adequate rolling stock capacity. Unfortunately, the latter is currently (in 2002) one of the bottlenecks in the service provision by the main Dutch railway operator NS Reizigers. Especially during the morning rush hours, many passengers cannot be transported according to the usual service standards because of a shortage of the rolling stock capacity. On the other hand, a more effective allocation of the available rolling stock capacity seems to be feasible, because there are also several trains with some slack capacity.

The effectiveness of the rolling stock capacity is determined mainly by the allocation of the train types and subtypes to the lines. Therefore, we describe in this paper a model that can be used to find an optimal allocation of train types and subtypes to the lines. This optimal allocation is more effective than the manually planned one, which is accomplished by minimizing the shortages of capacity during the rush hours.

The model is implemented in the modeling language OPL Studio 3.1, solved by CPLEX 7.0, and tested on several scenarios based on the 2001–2002 timetable of NS Reizigers. The results of the model were received positively, both by the planners and by the management in practice, because these results showed that a significant service improvement over the manually planned allocation can be achieved within a shorter throughput time of the involved part of the planning process.
Serum Sickness–Like Reaction Associated with Griseofulvin
Authors: Colton Roberta L , Amir Jacob , Mimouni Marc , Zeharia Avraham
Published: March 2004

OBJECTIVE

To describe a serum sickness—like reaction associated with griseofulvin in a child being treated for tinea capitis.

CASE SUMMARY

A previously healthy 5-year-old boy presented with tactile fever, rash on his legs and back, swelling of his toes and fingers, and leg pain. He was being treated at the time with griseofulvin for tinea capitis. Laboratory evaluation including immunologic workup revealed no abnormalities. Replacement of griseofulvin with itraconazole, along with an antihistamine and a nonsteroidal antiinflammatory drug, led to complete resolution of the patient's symptoms. An objective causality assessment revealed that the adverse reaction was probable.

DISCUSSION

Serum sickness—like reactions may occur 7–21 days following exposure to an offending agent. Clinical manifestations are similar to those of serum sickness, with fever, malaise, and cutaneous eruption. However, on laboratory workup, complement levels are normal. Management of serum sickness—like reaction includes replacing the offending agent and providing symptomatic relief.

CONCLUSIONS

Clinicians should be aware of the possibility of serum sickness—like reaction associated with griseofulvin therapy and consider the possibility when choosing between griseofulvin and newer, more expensive drugs.
Nephrotoxic Potential of Selective Cyclooxygenase-2 Inhibitors
Authors: Sandhu Gurbir K , Heyneman Catherine A
Published: March 2004

OBJECTIVE

To determine the relative nephrotoxic potential of cyclooxygenase (COX)-2 inhibitors.

DATA SOURCES

A MEDLINE search (1996—February 2004) identified clinical trials evaluating the nephrotoxicity of COX-2 inhibitors versus traditional nonsteroidal antiinflammatory drugs (NSAIDs). Key search terms included cyclooxygenase inhibitors, nonsteroidal antiinflammatory agents, nephrotoxicity, and chemically induced.

DATA SYNTHESIS

Three clinical trials determined that COX-2 inhibitors have similar adverse effects on the kidney when compared with nonselective NSAIDs, while 2 studies concluded that COX-2 inhibitors are less nephrotoxic than nonselective NSAIDs. All 5 trials utilized low numbers of subjects, short-term therapy, and surrogate markers of kidney damage.

CONCLUSIONS

COX-2 inhibitors may not offer distinct advantages over nonselective NSAIDs with respect to kidney function. Longer trials in patients with comorbidities are warranted. These agents should be used cautiously or not at all in patients with predisposing conditions.
HIV Infection: Point-of-Care Testing
Authors: Donovan Brian J , Rublein John C , Leone Peter A , Pilcher Christopher D
Published: March 2004

OBJECTIVE

To review the data regarding point-of-care testing for the diagnosis of HIV infection in the US.

DATA SOURCES

English-language literature was identified via MEDLINE (1980—August 2003) using key words such as rapid HIV tests and HIV antibody testing. Textbooks and other pertinent resources were also reviewed.

STUDY SELECTION AND DATA EXTRACTION

All articles identified through the data sources above were evaluated and reviewed if pertinent to the objective.

DATA SYNTHESIS

The Centers for Disease Control and Prevention (CDC) has announced an effort to expand currently recommended strategies to prevent new infections with HIV. The cornerstone of this initiative is the availability of the new rapid test for antibodies to HIV (OraQuick Rapid HIV-1 Antibody Test, OraSure Technologies, Bethlehem, PA). The effectiveness, sensitivity, and specificity of this test have been evaluated in a number of cross-sectional studies using previously or simultaneously performed HIV enzyme immunoassays with Western blot confirmation as a reference standard. Although there are several limitations to consider, results of these studies suggest that this test has comparable ability to detect HIV antibodies to other commercially available tests.

CONCLUSIONS

The OraQuick test is simple enough to be performed in many settings including those that facilitate achievement of the goals outlined by the CDC. Availability of this test should have a dramatic impact on HIV detection and prevention strategies.
Possible Gatifloxacin-Induced Hyperglycemia
Authors: Donaldson Amy R , Vandiver Jeremy R , Finch Christopher K
Published: March 2004

OBJECTIVE

To report a case of possible gatifloxacin-induced hyperglycemia in a nondiabetic middle-aged woman.

CASE SUMMARY

A 64-year-old Indian woman with an extensive cardiovascular history was admitted for urosepsis. On admission, her blood glucose was 117 mg/dL. She was empirically started on gatifloxacin 400 mg/day; after 3 days of gatifloxacin therapy, her blood glucose was 607 mg/dL. On day 4, therapy was changed to cefazolin for sensitive Escherichia coli and her blood glucose levels began to return to normal.

DISCUSSION

Although gatifloxacin has been previously reported as a potential cause of both hyper- and hypoglycemia, the exact mechanism is unknown. Several factors that may have been involved in our patient's hyperglycemia are discussed. She experienced hyperglycemic changes more rapidly than did the typical patients of previous reports. The Naranjo probability scale suggests a possible drug-related event.

CONCLUSIONS

The temporal relationship between gatifloxacin administration and the patient's hyperglycemia suggests an iatrogenic cause. Based on our experience and the product labeling, clinicians should be more aware of the blood glucose—altering effects of gatifloxacin.
Adefovir Dipivoxil in the Treatment of Chronic Hepatitis B
Authors: Rivkin Anastasia M
Published: March 2004

OBJECTIVE

To evaluate properties of the new acyclic nucleotide analog adefovir dipivoxil in the treatment of chronic hepatitis B (CHB).

DATA SOURCES

MEDLINE and PubMed searches from 1966 to December 2003 were performed with the headings chronic hepatitis B, interferon alfa-2b, lamivudine, liver transplant, and adefovir dipivoxil.

STUDY SELECTION AND DATA EXTRACTION

Randomized controlled studies and meta-analyses were evaluated in detail. A manual search was performed using references from retrieved primary literature, review articles, editorials, postgraduate course syllabi from national meetings, and textbooks. Emphasis was placed on controlled, prospective, randomized trials. National meeting abstract presentations were included if the information offered was original.

DATA SYNTHESIS

CHB is a major viral infection with an estimated 400 million carriers worldwide. Medications available to treat CHB include interferon alfa-2b and lamivudine, both agents having significant limitations. Adefovir dipivoxil is a novel nucleotide analog which, when given at 10 mg/day for 48 weeks, improved liver histology in 28% more patients with hepatitis B e antigen (HBeAg)-positive CHB, and in 31% more patients with HBeAg-negative CHB compared with placebo (p < 0.001). Additionally, adefovir dipivoxil therapy significantly improved virologic and biochemical parameters in both HBeAg-positive and -negative CHB patients. Adefovir dipivoxil offers important advantages over other CHB treatment options: it maintains activity against lamivudine-resistant CHB, has good efficacy against HBeAg-negative CHB, and has minimal adverse effects at the 10-mg/day Food and Drug Administration–approved dose.

CONCLUSIONS

Approved medications for the treatment of CHB have many limitations, and adefovir dipivoxil provides a new important option as an initial treatment, as well as treatment in lamivudine-resistant patients. THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-04-013-H01
Lepirudin in Heparin-Induced Thrombocytopenia and Extracorporeal Membranous Oxygenation
Authors: Dager William E , Gosselin Robert C , Yoshikawa Richard , Owings John T
Published: March 2004

OBJECTIVE

To report a case of intermediate-probability suspected heparin-induced thrombocytopenia (HIT) treated with lepirudin in a patient requiring continuous extracorporeal membranous oxygenation (ECMO).

CASE SUMMARY

A 17-year-old girl was admitted with multiple traumatic injuries including severe bilateral pulmonary contusions. Within 48 hours, she developed progressive pulmonary failure despite mechanical ventilation, and was placed on ECMO. Anticoagulation of the ECMO circuit was facilitated by unfractionated heparin (UFH). The platelet count of 116 × 103/mm3 after initiation of ECMO gradually decreased over 5 days to 44 × 103/mm3. On ECMO day 5, a highly positive enzyme-linked immunosorbent assay for HIT antibodies was reported, and the UFH infusion was discontinued. Lepirudin was immediately started with a bolus of 0.1 mg/kg, followed by an infusion of 0.12 mg/kg/h, with a target activated partial thromboplastin time (aPTT) ratio approximately 2 times control. The ECMO circuit was maintained without any unexpected bleeding complications or thrombosis for 6 additional days until the patient died secondary to pulmonary failure after ECMO was removed.

DISCUSSION

Use of ECMO typically requires continuous infusion of UFH to keep the circuit from clotting. In patients with HIT, alternative anticoagulation using a direct thrombin inhibitor may be warranted. Lepirudin was effectively used to maintain the circuit despite continued presence of heparin molecules impregnated into the ECMO circuit tubing. The aPTT was successfully used to monitor and adjust the lepirudin infusion.

CONCLUSIONS

In patients requiring ECMO in the presence of HIT, anticoagulation of the ECMO circuit may be accomplished using a continuous infusion of a direct thrombin inhibitor such as lepirudin.