bluuebunny/crossref_metadata_2025 huggingface dataset:
Acetaldehyde Induces Histamine Release from Human Airway Mast Cells to Cause Bronchoconstriction
Authors: Kawano Tetsuya , Matsuse Hiroto , Kondo Yuki , Machida Ikuko , Saeki Sachiko , Tomari Shinya , Mitsuta Kazuko , Obase Yasushi , Fukushima Chizu , Shimoda Terufumi , Kohno Shigeru
Published: June 2004

Backgrounds: Approximately half of the Japanese asthmatics experience exacerbation of asthma after alcohol consumption. We previously reported that this phenomenon is probably caused by histamine release from mast cells by acetaldehyde stimulation. However, no reports have described the effects of acetaldehyde on human airway mast cells. The purpose of the present study was to demonstrate acetaldehyde-induced histamine release from human airway mast cells with subsequent airway smooth muscle contraction and to investigate the ensuing mechanisms. Methods: Human tissue samples were prepared from the lungs resected from patients with lung cancer. The effect of acetaldehyde on airway muscle tone and the concentration of chemical mediators released in the organ bath were measured before and after acetaldehyde stimulation. Mast cells were prepared from lung parenchyma by the immunomagnetic method and then stimulated with acetaldehyde to determine the chemical mediators released. Results: Acetaldehyde (>3 × 10–4M) increased airway muscle tone, which was associated with a significant increase in the release of histamine, but not thromboxane B2 or cysteinyl-leukotrienes. A histamine (H1 receptor) antagonist completely inhibited acetaldehyde-induced bronchial smooth muscle contraction. Acetaldehyde also induced a significant histamine release from human lung mast cells and degranulation of mast cells. Conclusions: The present results strongly suggest that acetaldehyde stimulates human airway mast cells to release histamine, which may be involved in bronchial smooth muscle contraction following alcohol consumption.
Role of the Rhoa/Rho Kinase System in Flow-Related Remodeling of Rat Mesenteric Small Arteries in Vivo
Authors: Wesselman Jos P.M. , Kuijs Robin , Hermans J.J. Rob , Janssen Ger M.J. , Fazzi Gregorio E. , van Essen Helma , Evelo Chris T.A. , Struijker-Boudier Harry A.J. , De Mey Jo G.R.
Published: June 2004

In small arteries, a chronic blood flow reduction leads to inward hypotrophic remodeling, while a chronic blood flow elevation induces outward hypertrophic remodeling. The RhoA/Rho kinase system was shown to be modulated by shear stress, and to be involved in other kinds of vascular remodeling. The aim of this study was to investigate the role of RhoA/Rho kinase in flow-related small artery remodeling. Rat mesenteric small arteries were subjected to flow-modifying surgery. After 1, 2, 4, 16, and 32 days, the animals were sacrificed and small arteries were harvested. Messenger RNA was isolated and amplified. Using cDNA microarray analysis, the differential expression of >14,000 genes was analyzed, part of which was confirmed by RT-PCR. In vivo treatment with fasudil (3 mg/kg/day s.c.) was used to test the effect of Rho kinase inhibition. The main findings are that: (1) blood flow alteration modified the expression of approximately 5% of the genes by >2-fold, (2) flow reduction downregulated many RhoA-related cytoskeletal markers of smooth muscle cell phenotype, (3) many RhoA-related genes were rapidly (<1 day) regulated and (4) fasudil treatment potentiated the inward hypotrophic remodeling in response to chronically reduced flow. These results indicate the importance of the RhoA/Rho kinase system in flow-related small artery remodeling.
Magical Ideation – Defense Mechanism or Neuropathology?
Authors: te Wildt Bert Theodor , Schultz-Venrath Ulrich
Published: June 2004

Background: The major psychological stress factor in multiple sclerosis (MS) is loss of control of life. In MS patients with impaired cognition, magical ideation might be a characteristic way of thinking. Proof for this may be the high frequency of alternative treatments used by individuals with MS. The study investigates whether the level of magical ideation in MS patients is higher compared to healthy control subjects and, in case of positive confirmation, with which somatic and psychological features it is associated. Moreover, it is aimed to discuss the modalities of magical ideation in general. Sampling and Methods: A German version of the Magical Ideation Scale was validated with a group of 69 healthy subjects. Ninety-four MS patients were additionally assessed with the Dissociative Experience Scale, the Symptom-Check-List-90-Revised and 5 neuropsychological tests. Results: The Magical Ideation Scale did not reveal a significant difference between MS patients and healthy controls (p = 0.968). Among the MS patients, magical ideation shows a correlation neither with age nor with disability, but a positive correlation (p = 0.007; r = 0.329) with the grade of neuropsychological deficiency. Among the psychological parameters, the highest positive correlation with magical ideation was found in dissociation (p = 0.000; r = 0.520). Discussion: Magical ideation, sharing common features with dissociation, can be viewed as an early defense mechanism when perceiving a loss of control of life, particularly in early stages of MS. In late stages, when developing neuropsychological deficits, it may occur as a substitute for cognitive coping. The data may encourage clinicians to identify magical ideation. In young and previously diagnosed patients, it is important to acknowledge helplessness and support a rather rational way of coping. Training cognitive skills could be crucial to prevent older patients from losing touch with reality. More generally, the occurrence of a significant amount of magical ideation is discussed both as a psychological and a neurophysiologic regression of thinking.
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of an Orally Active Novel Camptothecin Analog, DRF‐1042, in Refractory Cancer Patients in a Phase I Dose Escalation Study
Authors: Chatterjee Arani , Digumarti Raghunadharao , Mamidi Rao N. V. S. , Katneni Kasiram , Upreti Vijay V. , Surath Anjna , Srinivas Maddali L. , Uppalapati Srihari , Jiwatani Sangeeta , Subramaniam Swaminathan , Srinivas Nuggehally R.
Published: June 2004

The objective of this study was to characterize the maximum tolerated dose (MTD), dose‐limiting toxicities (DLT), pharmacokinetics, and antitumor effects of DRF‐1042, a novel camptothecin analog, in refractory solid tumor patients. DRF‐1042 was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to 270 mg/m2. Adverse events were monitored following NCI‐CTC. Pharmacokinetics of lactone and total forms were determined using validated high‐performance liquid chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated applying World Health Organization (WHO) criteria. The 1st course was used to determine DLT and MTD. Twenty‐five patients received 73 courses of therapy. Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m2/day. AUC increased approximately linearly with dose. The t1/2 for lactone and total forms was 9.9 and 29 hours, respectively. AUCs correlated significantly with nadir leucopenia and grade 4 diarrhea. Two complete responses (CRs) and 2 partial responses (PRs) were observed. In addition, 4 stable diseases were observed. The recommended phase II dose is 80 mg/m2/day.
Pharmacokinetic Study of Mycophenolic Acid in Korean Kidney Transplant Patients
Authors: Cho Eun Kyung , Han Duck Jong , Kim Song Cheol , Burckart Gilbert J. , Venkataramanan Raman , Oh Jung Mi
Published: June 2004

The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA) in Korean kidney transplant recipients. Plasma MPA concentrations of 10 Korean kidney transplant recipients administered a lower dose of mycophenolate mofetil (MMF; 750 mg twice a day) were measured at 2 weeks of MMF therapy by high‐performance liquid chromatography (HPLC). The plasma MPA concentration‐time curve pattern of patients taking lower doses of MPA was consistent with previously reported profiles of patients taking the fully recommended doses. The plasma MPA concentration‐time curve was characterized by an early sharp peak within 1 hour and a small second peak in some patients at 4 to 12 hours postdose. The mean Cmax and AUC were 8.73 ± 4.65 μg/mL and 18.45 ± 4.25 μg•h/mL, respectively. The mean fraction of free MPA was 1.60% ± 0.23%. Patients' age, weight, body surface area, and renal function did not influence the AUC. The free fraction of MPA appeared not to be affected by serum albumin and renal function when creatinine clearance was above 40 mL/min. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that the concentrations of predose and 1‐ and 8‐hour postdose were positively correlated with AUC (r = 0.74545, p = 0.0133; r = 0.68485, p = 0.0289; and r = 0.63636, p = 0.0479, respectively). The pattern of the concentration‐time profile of MPA in Korean kidney recipients was similar to the results of other studies performed in Caucasians, although there was interindividual variability of AUC, Cmax, and tmax. MPA concentrations of predose and 1‐and 8‐hour postdose were positively correlated with AUC.
Multidisciplinary Opportunities and Challenges in NBIC
Authors: GOLLEDGE REGINALD G.
Published: June 2004

Abstract: This paper is divided into two primary sections: challenges and opportunities in the field of NBIC. Potential interactions between information technology and cognitive technology are principally discussed.
Single-Crystal Magnetic Study on Guest-Tunable Weak Ferromagnets [M{N(CN)2}2(pyrimidine)](guest) (M = Fe, Co)
Authors: Takagami Naomi , Ishida Takayuki , Nogami Takashi
Published: June 2004

Low-temperature magnets derived from [M{N(CN)2}2(pm)] (M = FeII, CoII) have guest molecules incorporated in the clearance of the three-dimensional framework, where pm stands for pyrimidine. A pm molecule in [Fe{N(CN)2}2(pm)](pm) (1) was characterized as a guest by means of X-ray crystallographic analysis. The guest molecules as well as the host N(CN)2 skeletons are disordered in [Fe{N(CN)2}2(pm)](guest) (guest = EtOH (2), n-PrOH (3), 1/2 n-BuOH (4)) and also in [Co{N(CN)2}2(pm)](guest) (guest = EtOH (5), n-PrOH (6)). The ac and dc magnetic susceptibility measurements on randomly oriented polycrystalline samples of 1–6 revealed that they were weak ferromagnets (canted antiferromagnets) below TN. The single-crystal magnetization measurements clarified the TN’s and the cant angles at 2 K as follows: TN = 5.6 K, θ = 1.3°(H || c) for 1; TN = 3.3 K, θ = 16°(H || c) for 2; TN = ca. 2 K, θ = 7.1°(H || b) for 5. The magnetic ground state seems to be related with single-ion anisotropy of the metal ions and the spin canting may take place as a combined result of the axial or in-plane anisotropy and antiferromagnetic interaction. The incorporated guest molecule tunes the single-ion anisotropy of the host metal ions, and consequently the magnetic phase transition phenomena were drastically different depending on the guest molecules.
Synthesis and Characterization of New trans
N,N′-Disubstituted Macrocyclic “tet a” Ligands and Their Copper(II) and Nickel(II) Complexes: Structural, Electrochemical, Magnetic, and Catalytic Studies
Authors: Sengottuvelan Nallathambi , Saravanakumar Duraisamy , Narayanan Vengidusamy , Kandaswamy Muthusamy , Chinnakali Kandaswamy , Senthilkumar Gopal
Published: June 2004

New trans-disubstituted macrocyclic ligands (L1), trans-1,8-[N,N′-bis{(3-formyl-2-hydroxy-5-methyl)benzyl}]-1,4,8,11-tetraaza-5,5,7,12,12,14-hexamethylcyclotetradecane, and (L2), 1,8-[N,N′-bis{(3-formyl-2-hydroxy-5-methyl)benzyl}]-4,11-dimethyl-1,4,8,11-tetraaza-5,5,7,12,12,14-hexamethylcyclotetradecane, were synthesized. The ligands were characterized by elemental analysis, IR, 1H and 13C NMR spectral analyses. The ligand L1 crystallized as monoclinic in the space group P21/n, and the final R-value was found to be 0.062. Copper(II) and nickel(II) complexes of these ligands were prepared and characterized by elemental analysis, IR, UV–visible, FAB-mass spectral studies. Electrochemical studies of the nickel(II) complexes show one-electron quasireversible reduction around −1.00 to −1.13 V and one-electron quasireversible oxidation around 1.00 to 1.14 V. The copper(II) complexes show one-electron quasireversible reduction around −0.93 to −1.10 V. ESR spectral studies of the copper(II) complexes show hyperfine splitting with a g|| value of 2.31, a g⊥ value of around 2.02 and an A value of 160 G. The magnetic moment values (μeff) of the Cu(II) complexes fall in the range of 1.71 to 1.72 B.M. at room temperature (298 K). The rate-constant values of the catalytic hydrolysis of p-nitrophenyl phosphate for the copper(II) complexes were in the range 6.3 × 10−3 to 12.2 × 10−3 min−1 and for the nickel(II) complexes in the range 10 × 10−3 to 14 × 10−3 min−1. The rate-constant values of the catalytic oxidation of catechol to o-quinone were in the range 9.4 × 10−3 to 13.4 × 10−3 min−1 for the copper(II) complexes. The copper(II) and nickel(II) complexes of ligand L2 have higher catalytic activity than that of ligand L1.
Reaction of Mixed-Ligand Iron–Sulfur Cluster [Fe4(Cp*)3(Ph2C2S2)(μ3-S)3(μ3-S2)] (Cp* = C5Me5) with Methyl Iodide. Synthesis, Structure, and Redox Behavior of [Fe4(Cp*)3(Ph2C2S2)(μ3-S)3(μ3-S2Me)]
Authors: Inomata Shinji , Hitomi Keiichi , Ogino Hiroshi
Published: June 2004

The reaction of the mixed-ligand iron–sulfur cluster [Fe4(Cp*)3(Ph2C2S2)(μ3-S)3(μ3-S2)] ([3]) (Cp* = C5Me5) with iodomethane gave a methylated cluster, [Fe4(Cp*)3(Ph2C2S2)(μ3-S)3(μ3-S2Me)]I ([4]I), in 60% yield. The anion exchange of [4]I with KPF6 gave [4]PF6 as a pure sample. A similar treatment of [3] using iodoethane afforded an ethylated cluster, [Fe4(Cp*)3(Ph2C2S2)(μ3-S)3(μ3-S2Et)]I ([5]I), and oxidized parent cluster [3]I. The reaction of [3] with 2-iodopropane did not give an alkylated cluster. An unreacted cluster [3] was recovered with a small amount of oxidized cluster [3]I. The molecular structure of [Fe4(Cp*)3(Ph2C2S2)(μ3-S)3(μ3-S2Me)] ([4]), which was obtained by the reduction of [4]PF6 with cobaltocene, was determined by an X-ray diffraction study. Crystallographic data are: Monoclinic, P21/a, a = 21.707(2) Å, b = 21.382(2) Å, c = 11.433(1) Å, β = 98.98(1)°, V = 5241.5(9) Å3, Z = 4, and R = 0.067 for 7412 reflections with |Fo| > 3σ(Fo). The methyl group transferred from MeI is located on the singly ligating sulfur atom in the disulfide ligand of the parent cluster [3]. A cyclic voltammogram of [4]PF6 in 0.1 mol dm−3 tetrabutylammonium tetrafluoroborate–CH3CN showed five reversible one-electron redox waves at E1/2 = +1.42 V, +0.92 V, +0.41 V, −0.38 V, and −1.22 V vs SCE, corresponding to 4+/3+, 3+/2+, 2+/1+, 1+/0, and 0/1− charged cluster couples, respectively. An irreversible two-electron reduction wave was also observed at Epc = −1.97 V vs SCE.
Origin of Regioselectivity in Photocycloaddition Reactions of 2-Cyclohexenone with Cycloalkenecarboxylates
Authors: Odo Yuka , Shimo Tetsuro , Hori Kenji , Somekawa Kenichi
Published: June 2004

The regiochemical results in [2 + 2]photocycloaddition of 2-cyclohexenone (1) with 1-cycloalkenecarboxylates (2–4) significantly changed from head-to-head (hh) to head-to-tail (ht) adducts depending on increments of the ring-size, from four to six, of the carboxylates. The root of the drastic regioselective change was inferred from the transition state (TS) analysis of the triplet reactions, including the back-reaction at the PM5 and B3LYP levels. The TS energy of the first step (TS1) is the most important factor for this reaction. The change in TS energies at hh adducts was larger than that at ht adducts. For more detailed analysis, the TS energies of the hh and ht reactions (at the three reactions) were partitioned to the two reactant deformation (Edf) and the interaction (or repulsion, Eint) energies. The Edf and Eint energy changes were found to be dependent on the ring-size of the 1-cycloalkenecarboxylates 2–4. Thus, since the larger ring of 4 has relatively higher TS1 and deformation energies for giving the hh adduct, they may cause the preferential formation of the ht adduct, and result in the significant changes in the ht/hh ratio owing to the ring-size. The root of the significant hh diminution may be the dipole–dipole repulsion between the enone carbonyl and larger carboxylate (4) moieties. The improved PM5 and B3LYP/6-31+G(d) calculations are effective and economical for disclosing the origin of regioselectivity in [2 + 2]photocycloadditions.
Mechanistic Studies on Nitrosation–Deaminocyclization of Mono-Carbamoylated Vicinal Amino Alcohols and Diols: A New Preparative In Situ Formation of Ethanediazo Hydroxide for the Ethylation of Carboxylates under Mild Conditions
Authors: Suzuki Masumi , Sugai Takeshi
Published: June 2004

While the cyclization of N-carbamoylamino alcohols into oxazolidinones via the activation with NO+ underwent smoothly, we found that similar reactions of vicinal diol monocarbamates were very slow. Mechanistic studies by means of time-resolved IR measurements of the former reaction suggested that the initial O-nitrosation was the rate-determining step. Indeed, the introduction of an ethyl group on the nitrogen terminus of diol monocarbamate promoted the desired cyclic carbonate formation. The concomitantly formed ethanediazo hydroxide, the precursor of the protonated form of diazoethane, was evidenced by trapping with p-nitrobenzoic acid as an ethyl ester. The formation of ethyl ester accelerates the reaction in an irreversible manner. Based on an elaboration of the substrates and reaction conditions, 2,3-dimethyl-2,3-butanediol mono-N-ethyl-N-nitrosocarbamate, which is easily prepared in situ from the corresponding ethylcarbamate and t-butyl nitrite, was developed as a new ethylation reagent of various carboxylic acids under mild conditions.
Synthesis and Gas Sensing Properties of Polypyrrole/MoO3-Layered Nanohybrids
Authors: Matsubara Ichiro , Hosono Kouta , Murayama Norimitsu , Shin Woosuck , Izu Noriya
Published: June 2004

Intercalative hybrid materials, comprised of polypyrrole (PPy) chains interleaved with the layers of MoO3, have been synthesized using concomitant ion exchange reaction. The (PPy)xMoO3-pressed pellets show a semiconducting-like transport with an activation energy of 0.2 eV. The MoO3 host layers play a dominant role in the determination of the transport properties of (PPy)xMoO3. The (PPy)xMoO3-pressed pellets show a distinct response to volatile organic compounds (VOCs) by increasing their electrical resistivity, which could be induced by the incorporation of VOC molecules into the interlayers of (PPy)xMoO3. (PPy)xMoO3 exhibits higher sensitivities to polar analytes such as formaldehyde and acetaldehyde, whereas it shows almost no response to toluene and benzene.
A Branch-and-Price Algorithm for Multistage Stochastic Integer Programming with Application to Stochastic Batch-Sizing Problems
Authors: Lulli Guglielmo , Sen Suvrajeet
Published: June 2004

In this paper, we present a branch-and-price method to solve special structured multistage stochastic integer programming problems. We validate our method on two different versions of a multistage stochastic batch-sizing problem (SBSP). One version adopts a recourse formulation, and the other is based on probabilistic constraints. Our algorithmic approach is applicable to both formulations. Our computational results suggest that both classes of problems can be solved using relatively few nodes of a branch-and-price tree. The success of our approach calls for extensions in methodology as well as applications.
Knowledge Sourcing Effectiveness
Authors: Gray Peter H. , Meister Darren B.
Published: June 2004

Much of the knowledge management (KM) literature focuses on ways to increase the volume of knowledge available to employees, ensure its quality, and improve its accessibility. Such supply-side arguments are limited to the extent that they do not address the demand for knowledge within organizations. This paper takes a novel approach to understanding how access to others' knowledge produces benefits by studying the extent to which individuals intentionally access each other's expertise, experience, insights, and opinions, which we term knowledge sourcing. A general model of knowledge sourcing, including contextual and dispositional antecedents and learning outcomes, is proposed and validated using survey data from a global organization. Knowledge sourcing explains a significant proportion of individuals' learning outcomes, but the strength of this effect is moderated both by the strength of individuals' learning orientations and the degree to which they find their jobs to be intellectually demanding. For researchers, this study extends existing knowledge by proposing, testing, and validating a new way to understand an important KM issue in organizations. Practitioners can use these findings to evaluate existing KM efforts and better target future KM interventions towards those individuals most likely to benefit.
Modifying Variability and Correlations in Winner-Take-All Contests
Authors: Gaba Anil , Tsetlin Ilia , Winkler Robert L.
Published: June 2004

We consider contests with a fixed proportion of winners based on relative performance. Special attention is paid to winner-take-all contests, which we define as contests with relatively few winners receiving relatively large awards, but we consider the full range of values of the proportion of winners. If a contestant has the opportunity to modify the distribution of her performance, what strategy is advantageous? When the proportion of winners is less than one-half, a riskier performance distribution is preferred; when this proportion is greater than one-half, it is better to choose a less risky distribution. Using a multinormal model, we consider modifications in the variability of the distribution and in correlations with the performance of other contestants. Increasing variability and decreasing correlations lead to improved chances of winning when the proportion of winners is less than one-half, and the opposite directions should be taken for proportions greater than one-half. Thus, it is better to take chances and to attempt to distance oneself from the other contestants (i.e., to break away from the herd) when there are few winners; a more conservative, herding strategy makes sense when there are many winners. Our analytical and numerical results indicate that the probability of winning can change substantially as variability and/or correlations are modified. Furthermore, in a game-theoretic setting in which all contestants can make modifications, choosing a riskier (less risky) performance distribution when the proportion of winners is low (high) is the dominant best-response strategy. We briefly consider some practical issues related to the recommended strategies and some possible extensions.
On the Coordinated Random Group Replacement Policy in Multivariate Repairable Systems
Authors: Li Haijun , Xu Susan H.
Published: June 2004

We study a system with multiple components and preventive maintenance. At predetermined times, some of the components are replaced with new ones. We permit the set of components that are chosen for replacement to be random and study the effect of dependency in this selection. For example, we show that it is often better to have simultaneous replacements of components, rather than replacing each component independently of the others. We also show that preventive maintenance only makes sense for components whose lifetimes are new-better-than-used (NBU).
An Exact Method for the Car Pooling Problem Based on Lagrangean Column Generation
Authors: Baldacci Roberto , Maniezzo Vittorio , Mingozzi Aristide
Published: June 2004

Car pooling is a transportation service organized by a large company which encourages its employees to pick up colleagues while driving to/from work to minimize the number of private cars travelling to/from the company site. The car pooling problem consists of defining the subsets of employees that will share each car and the paths the drivers should follow, so that sharing is maximized and the sum of the path costs is minimized. The special case of the car pooling problem where all cars are identical can be modeled as a Dial-a-Ride Problem. In this paper, we propose both an exact and a heuristic method for the car pooling problem, based on two integer programming formulations of the problem. The exact method is based on a bounding procedure that combines three lower bounds derived from different relaxations of the problem. A valid upper bound is obtained by the heuristic method, which transforms the solution of a Lagrangean lower bound into a feasible solution. The computational results show the effectiveness of the proposed methods.
Stakeholder Theory and “The Corporate Objective Revisited”: A Reply
Authors: Sundaram Anant K. , Inkpen Andrew C.
Published: June 2004

Freeman et al. (2004) offer a spirited rebuttal to our paper “The Corporate Objective Revisited” from the perspective of stakeholder theory. However, they fall short in making a case against the logic of shareholder value maximization. The authors confound issues of “value” and “values,” ignore the rich history of scholarship on related questions, and perhaps misinterpret some of our core arguments. Most importantly, proponents of stakeholder views such as Freeman et al. appear to be unable to go beyond critiques of the shareholder view by failing to offer an empirically supportable alternative theory.
Introduction to the “Corporate Objective Revisited” Exchange
Authors: Walsh James P.
Published: June 2004

Corporate scandals and abuses of various kinds grab the headlines. Reform initiatives quickly follow outrage. The goal is to constrain our firms' ability to destroy value and lives, while at the same time enabling them to produce and deliver high-quality and profitable goods and services in a very competitive global marketplace. Less obvious but no less important, civil society is increasingly asking corporations to invest directly in social life. Regardless of their productive capabilities, firms can field requests to invest in education, health care, infrastructure, and the like. Sometimes the two ambitions seem to be quite compatible, while at other times they seem to be at odds. Leading a business that is at once socially responsive and economically competitive is a daunting managerial challenge. The theoretical challenge posed by these sometimes competing and sometimes complementary demands is no less daunting.

Since the rise of the first corporations two thousand years ago, we have been trying to develop a theory of the firm that explains and guides firm behavior. Sundaram and Inkpen enter this complex and charged world to make a case for a theory of the firm grounded in the pursuit of shareholder wealth. Freeman, Wicks, and Parmar will not let their view go unchallenged. They offer a spirited reply. The exchange embodies everything our Crossroads section can be. We are proud to provide a home for this very thoughtful exchange. This is arguably the most important theoretical and practical issue confronting us today. While we gave Sundaram and Inkpen the last word, we know that the debate is far from over. Indeed, we invite others to think hard about these issues and develop their own point of view. The stakes are enormous.
A Controlled Trial of a Critical Pathway for Treating Community‐Acquired Pneumonia: The CAPITAL Study
Authors: Feagan Brian G.
Published: June 2004

Recent clinical trials in patients with community‐acquired pneumonia (CAP) demonstrated that switching from intravenous to oral antibiotic therapy is safe once clinical improvement is evident, thereby facilitating early hospital discharge. This study evaluated the use of a critical pathway to improve the efficiency of treating CAP in 1743 patients at 19 teaching and community hospitals in Canada. Hospitals were randomized to continue conventional management of CAP (10 hospitals) or implement a critical pathway (9 hospitals). The main clinical outcome measure was patients' scores (assessed 6 wks after hospital presentation) on the Short‐Form 36 Physical Component Summary, a quality‐of‐life questionnaire. Secondary clinical outcome measures included occurrence of complications, readmission rates, and mortality. The primary economic outcome measure was resource utilization, measured by the number of bed days/patient managed (BDPM). Clinical outcomes were good in both groups, with no significant differences between the two management strategies. However, use of the clinical pathway was associated with a 1.7‐day reduction in BDPM and fewer admissions of low‐risk patients.
New Directions in Antiinfective Therapy for Community‐Acquired Pneumonia in the Emergency Department
Authors: Moran Gregory J.
Published: June 2004

The emergency department is becoming an increasingly important setting for the management of community‐acquired pneumonia (CAP). This trend reflects the shortened hospital stays and decreased mortality among elderly hospitalized patients resulting from rapid administration of antimicrobials. In addition, decisions about the site of care (inpatient vs outpatient) and antimicrobial therapy frequently are made in the emergency department. Recent research and subsequent clinical guidelines may help with these decisions. For example, recently issued guidelines, such as those of the Infectious Diseases Society of America and the American Thoracic Society, suggest that selection of antimicrobials for CAP (which is typically empiric) should be based on the potential pathogens and likelihood of antimicrobial resistance. Macrolides and tetracyclines are recommended in younger patients with mild‐to‐moderate disease. Patients with more severe disease and those at risk for drug‐resistant pathogens should be treated with broad‐spectrum therapy, such as a newer fluoroquinolone or a cephalosporin plus a macrolide. When hospitalization is required, early switch from intravenous to oral therapy, followed by early discharge, can be a highly successful strategy. Antimicrobials that are available in both intravenous and oral formulations, such as the newer fluoroquinolones (e.g., levofloxacin and gatifloxacin), can simplify switch therapy. For outpatients, an initial long‐acting parenteral dose of azithromycin, ceftriaxone, or levofloxacin followed by oral therapy is an effective protocol. In addition, use of a prediction rule to identify low‐risk patients with CAP may help guide decisions about the need for hospital admission.
Failed Challenge with Quetiapine after Neuroleptic Malignant Syndrome with Conventional Antipsychotics
Authors: Hatch Carie D. , Lund Brian C. , Perry Paul J.
Published: June 2004

Neuroleptic malignant syndrome (NMS) is an uncommon but potentially life‐threatening adverse effect associated with conventional antipsychotic agents. The syndrome is characterized by muscular rigidity, hyperpyrexia, altered consciousness, and autonomic dysfunction. Few cases of quetiapine‐induced NMS have been reported. A 54‐year‐old man was unsuccessfully challenged with quetiapine after conventional antipsychotic‐induced NMS.
Extended‐Spectrum β‐Lactamases: Epidemiology, Detection, and Treatment
Authors: Nathisuwan Surakit , Burgess David S. , Lewis James S.
Published: June 2004

Extended‐spectrum β‐lactamases (ESBLs) are extremely broad spectrum β‐lactamase enzymes found in a variety of Enterobacteriaceae. Most strains producing these β‐lactamases are Klebsiella pneumoniae, other Klebsiella species (i.e., K. oxytoca), and Escherichia coli. When producing these enzymes, organisms become highly effective at inactivating various β‐lactam antibiotics. In addition, ESBL‐producing bacteria are frequently resistant to many classes of antibiotics, resulting in difficult‐to‐treat infections. Other problems due to ESBL‐producing bacteria are difficulty in detecting the presence of ESBLs, limited treatment options, and deleterious impact on clinical outcomes. Clinicians should be familiar with the clinical significance of these enzymes and potential strategies for dealing with this growing problem.
Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Authors: Adkison Julie D. , Konzem Sherri L.
Published: June 2004

Patients with chronic obstructive pulmonary disease are at high risk for acute exacerbations. Strategies that may prevent exacerbations are smoking cessation, pulmonary rehabilitation, and influenza vaccination. Therapy includes bronchodilators, corticosteroids, and antibiotics. Rapid‐acting β2‐agonists are bronchodilating agents of choice. Ipratropium should be considered in patients who fail or cannot tolerate β2‐agonists. Data do not support combining anticholinergics and β2‐agonists in acute exacerbations; however, new data do support systemic corticosteroids for their role in reducing airway inflammation. Antibiotics should be included in the regimen if two of the three following are present: increased dyspnea, increased sputum volume, and increased sputum purulence. Many exacerbations may be caused by viruses or noninfective sources, in which case antibiotics are not indicated. Oxygen administration with or without assisted ventilation may be required for short‐term management.
In Vitro Antifungal Susceptibility Testing
Authors: Hoffman Holly L. , Pfaller Michael A.
Published: June 2004

With the rising frequency of fungal infections, as well as increasing reports of resistance to antifungal agents, it is imperative that clinically applicable antifungal susceptibility testing be available. In 1997 the National Committee for Clinical Laboratory Standards published standard guidelines for antifungal susceptibility testing of Candida sp and Cryptococcus neoformans with amphotericin B, flucytosine, fluconazole, itraconazole, and ketoconazole. Although the methods are standard, they are time consuming, can be difficult to interpret, and are approved only for testing limited organisms and drugs. Modifications to the methods and alternative approaches have been proposed to make these tests more convenient and efficient, applicable to a greater number of species, and appropriate for performing in the clinical laboratory.
A Comprehensive Review of MDMA and GHB: Two Common Club Drugs
Authors: Teter Christian J. , Guthrie Sally K.
Published: June 2004

“Club drugs” have become alarmingly popular. The use of 3,4‐methylenedioxymethamphetamine (MDMA, Ecstasy) and γ‐hydroxybutyrate (GHB), in particular, has increased dramatically from 1997–1999. The pharmacokinetics of MDMA and GHB appear to be nonlinear, making it difficult to estimate a dose‐response relationship. The drug MDMA is an amphetamine analog with sympathomimetic properties, whereas GHB is a γ‐aminobutyric acid analog with sedative properties. Symptoms of an MDMA toxic reaction include tachycardia, sweating, and hyperthermia. Occasional severe sequelae include disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Treatment includes lowering the body temperature and maintaining adequate hydration. Symptoms of GHB intoxication include coma, respiratory depression, unusual movements, confusion, amnesia, and vomiting. Treatment includes cardiac and respiratory support. Because of the popularity of these agents and their potentially dangerous effects, health care professionals must be familiar with these substances and the treatment options for patients who present with symptoms of a toxic reaction.
A Comparison of the Steady‐State Pharmacokinetics and Safety of Abacavir, Lamivudine, and Zidovudine Taken as a Triple Combination Tablet and as Abacavir plus a Lamivudine‐Zidovudine Double Combination Tablet by HIV‐1‐Infected Adults
Authors: Crémieux Anne‐Claude , Katlama Christine , Gillotin Catherine , Demarles Didier , Yuen Geoffrey J. , Raffi Francois ,   AZL10002 Study Group
Published: June 2004

Study Objective. To investigate the steady‐state pharmacokinetics of a triple combination tablet containing abacavir (ABC) 300 mg, lamivudine (3TC) 150 mg, and zidovudine (ZDV) 300 mg taken twice/day, and those of ABC 300 mg twice/day plus a double combination tablet containing 3TC 150 mg and ZDV 300 mg twice/day (ABC‐COM).

Design. Open‐label, crossover study.

Setting. Two hospital‐based clinical research units.

Patients. Twelve men infected with human immunodeficiency virus‐1.

Intervention. Steady‐state pharmacokinetics of ABC, 3TC, and ZDV were assessed after dosing with ABC‐COM and the triple combination tablet.

Measurements and Main Results. Steady‐state pharmacokinetics of ABC, 3TC, and ZDV were similar for the triple combination tablet versus ABC‐COM for the following: geometric mean (GM) area under the serum concentration‐time curve, ABC 6.08 versus 5.87, 3TC 5.51 versus 5.53, and ZDV 1.38 versus 1.46 μg·hr/ml; GM maximum serum concentration (Cmax‐ss), ABC 3.09 versus 3.19, 3TC 1.26 versus 1.40, and ZDV 1.19 versus 1.15 μg/ml; median time to Cmax‐ss, ABC 0.75 versus 0.75, 3TC 1.50 versus 1.24, and ZDV 0.75 versus 0.75 hours; and GM oral clearance, ABC 51 versus 49, 3TC 27 versus 27, and ZDV 217 versus 206 L/hour. The GM half‐lives of ABC and ZDV were similar for both treatments, 1.69 versus 1.58 and 2.30 versus 2.08 hours, respectively.

Conclusion. Steady‐state pharmacokinetics of ABC, 3TC, and ZDV were similar in patients who took them as ABC‐COM or as a triple combination tablet.
Safety and Effectiveness of Ibutilide in a Community Hospital
Authors: Taylor Charles T. , Donaldson Amy R.
Published: June 2004

To determine the safety and effectiveness of ibutilide, we conducted a retrospective study of patients in a community hospital from December 1997‐January 2000, reviewing hospital and pharmacy records for 12 inpatients (aged 68 ± 13 yrs) receiving ibutilide for atrial fibrillation or flutter. The cumulative conversion rate with ibutilide 0.012 ± 0.004 mg/kg was 58%. Serious cardiovascular adverse events were documented in six patients; of those patients, five had baseline QTc intervals above 440 msec, two experienced ventricular fibrillation, and four experienced symptomatic bradycardia (range 49–60 beats/minute) requiring medical intervention. The effectiveness of ibutilide was similar to that found in previous studies. However, more complications were seen in this setting where ibutilide was used infrequently and without stringent patient selection criteria or standardized administration protocols. To ensure optimal patient care, institutions should consider implementing guidelines or education strategies to reduce the potential for serious adverse effects associated with improper screening, dosing, and monitoring of patients receiving ibutilide.
Colestipol‐Induced Hepatotoxicity
Authors: Sirmans Susan M. , Beck Joni K. , Banh Hoan Linh , Freeman Dale A.
Published: June 2004

A 65‐year‐old man with type IIa dyslipidemia who received flavored colestipol granules 2 scoops/day for 3 months developed asymptomatic hepatotoxicity. Several of his liver enzymes were elevated 10 times the upper limit of normal. One week after discontinuing colestipol, serum transaminases fell dramatically, with some returning to normal limits. Four weeks after colestipol was discontinued, all liver function tests were normal. Rechallenge was not attempted. Other potential causes of hepatocellular injury were evaluated. Bile acid‐binding resins commonly are administered to treat type IIa dyslipidemia. Despite extensive use of the resins, significant elevations of transaminase levels are rare. Because the exact mechanism of bile acid resin‐induced hepatotoxicity is unknown, high‐risk patients may require liver function test monitoring and education on hepatotoxic side effects.
Economic Impact of Community Pharmacist Intervention in Cholesterol Risk Management: An Evaluation of the Study of Cardiovascular Risk Intervention by Pharmacists
Authors: Simpson Scot H. , Johnson Jeffrey A. , Tsuyuki Ross T.
Published: June 2004

The Study of Cardiovascular Risk Intervention by Pharmacists, a randomized, controlled trial in over 50 community pharmacies in Alberta and Saskatchewan, Canada, demonstrated that a pharmacist intervention program improved cholesterol risk management in patients at high risk for cardiovascular disease. In a substudy, costs and consequences were analyzed to describe the economic impact of the program. Two perspectives were taken: a government‐funded health care system and a pharmacy manager. Costs were reported in 1999 Canadian dollars. Incremental costs to a government payor and community pharmacy manager were $6.40/patient and $21.76/patient, respectively, during the 4‐month follow‐up period. The community pharmacy manager had an initial investment of $683.50. The change in Framingham risk function for the intervention group from baseline also was reported. The 10‐year risk of cardiovascular disease decreased from 17.3% to 16.4% (p<0.0001) during the 4 months. The intervention program in this study led to a significant reduction in cardiovascular risk in the intervention group during the 4‐month follow‐up period. The incremental cost to provide the program appeared minimal from both government and pharmacy manager perspectives. It is hoped that these results could support negotiations for reimbursement of clinical pharmacy services with payors.
Bioavailability of the Oral Selective Phosphodiesterase 4 Inhibitor Cilomilast
Authors: Zussman Barry D. , Davie Christopher C. , Kelly John , Murdoch Robert D. , Clark David J. , Schofield J. Paul , Walls Christine , Birrell Claire , Webber Dawn , Quinlan Judith , Ritchie Sally Y. , Carr Alison
Published: June 2004

Study Objective. To determine the absolute bioavailability of cilomilast, and assess the effects of food, dosing time, and coadministration of antacid agents on its bioavailability and pharmacokinetics in healthy volunteers.

Setting. Clinical pharmacology unit.

Design. Five prospective pharmacokinetic studies: one single‐blind, dose‐escalating, placebo‐controlled trial; four open‐label, randomized studies.

Subjects. Ninety‐six healthy adult volunteers who were nonsmokers.

Intervention. In the first study, four subjects received intravenous cilomilast 1, 2, and 4 mg. In the second study, 16 subjects received oral cilomilast 15 mg or intravenous cilomilast 4 mg. In the other three studies, a total of 76 subjects were given single oral 15‐mg doses; one study compared its effects in fed versus fasted subjects, one looked for differences of morning versus evening dosing, and one examined coadministration with aluminum hydroxide‐magnesium hydroxide.

Measurements and Main Results. After intravenous administration of cilomilast, plasma concentrations increased in an approximately dose‐proportional manner; the half‐life, approximately 6.5 hours, was dose independent. Cilomilast clearance and volume of distribution were small. After oral dosing, the absolute bioavailability was consistently close to 100%. Absorption was slower in fed subjects than in fasted (median 2‐hr delay in time to reach maximum plasma concentration, average 39% reduction in maximum plasma concentration), but the area under the concentration‐time curve from time zero to infinity (systemic availability) was unaffected. Pharmacokinetic parameters were not influenced by time of dosing or coadministration of antacid.

Conclusion. The absolute bioavailability of oral cilomilast was 100%; it was not adversely affected by time of dosing or coadministration with food or antacid.
Hyperbilirubinemia during Quinupristin‐Dalfopristin Therapy in Liver Transplant Recipients: Correlation with Available Liver Biopsy Results
Authors: Linden Peter K. , Bompart François , Gray Sharon , Talbot George H.
Published: June 2004

Study Objective. To review the liver histopathology in transplant recipients who developed hyperbilirubinemia during therapy with quinupristin‐dalfopristin, a new streptogramin antibiotic, and to ascertain whether objective histologic evidence of adverse drug effect could be correlated to serum bilirubin levels.

Design. Retrospective analysis.

Setting. University of Pittsburgh Medical Center.

Patients. From a database of 34 liver recipients who received quinupristin‐dalfopristin for vancomycin‐resistant Enterococcus faecium infection who were prospectively enrolled in a multicenter, open‐label, emergency‐use protocol, the data for a subset of 25 patients who underwent one or more liver biopsies during therapy were reviewed for this study.

Interventions. Quinupristin‐dalfopristin was administered intravenously at 7.5 mg/kg every 8 hours. Available serum bilirubin levels from before, during, and 1 week after therapy were tabulated. Liver biopsy results obtained within 1 week before and during therapy were retrospectively reviewed. Histopathologic results were characterized and correlated to bilirubin level.

Measurements and Main Results. Cholestatic changes were already present in 15 of 17 patients who underwent biopsy before therapy. During therapy, the most common findings from 40 biopsies (25 patients) were cholestasis (33 biopsies), acute rejection (10), and periportal inflammation (8). There was no evidence of drug‐specific histopathologic injury.

Conclusion. Hyperbilirubinemia in these patients was likely multifactorial and most frequently due to sepsis and prior graft injury.
Drug Therapy and Prevalence of Erectile Dysfunction in the Massachusetts Male Aging Study Cohort
Authors: Derby Carol A. , Barbour Marilyn M. , Hume Anne L. , McKinlay John B.
Published: June 2004

Study Objective. To examine the association of commonly used drugs with erectile dysfunction (ED) at two time points.

Design. Population‐based, cross‐sectional, survey analysis.

Participants. Randomly selected cohort of men in the Massachusetts Male Aging Study (MMAS) that included 1476 men for the baseline (1987–1989) and 922 for the follow‐up (1995–1997) analyses.

Intervention. Crude associations between specific drug categories were examined with X2 statistics. Logistic regression analysis was used to separate the effect of drugs from the influence of heart disease, hypertension, untreated diabetes, or depressive symptoms.

Measurements and Main Results. In the MMAS, medical history, current drug use, and erectile function status were ascertained with in‐home interviews. In unadjusted analyses, thiazide and nonthiazide diuretics, β‐blockers, calcium channel blockers, angiotensin‐converting enzyme inhibitors, benzodiazepines, digitalis, nitrates, 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors, and histamine2 receptor antagonists were associated with prevalent ED. Adjustment for comorbidities and health behaviors attenuated these associations, with only nonthiazide diuretics and benzodiazepines remaining statistically significant.

Conclusion. Several common drugs may increase prevalence of ED; however, additional data from larger populations are needed to determine whether these associations are independent of underlying health conditions and to explore the effects of dosage and duration of use.