bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vitro Selection and In Vivo Efficacy of Piperazine- and Alkanediamide-Linked Bisbenzamidines against
Pneumocystis
Pneumonia in Mice
Authors: Cushion Melanie T. , Walzer Peter D. , Ashbaugh Alan , Rebholz Sandra , Brubaker Ronald , Vanden Eynde Jean Jacques , Mayence Annie , Huang Tien L.
Published: June 2006

Bisbenzamidines, such as pentamidine isethionate, are aromatic dicationic compounds that are active against
Pneumocystis
and other microbes but are oftentimes toxic to the host. To identify potential anti-
Pneumocystis
agents, we synthesized bisbenzamidine derivatives in which the parent compound pentamidine was modified by a 1,4-piperazinediyl, alkanediamide, or 1,3-phenylenediamide moiety as the central linker. Several of the compounds were more active against
P. carinii
and less toxic than pentamidine in cytotoxicity assays. For this study, we evaluated nine bisbenzamidine derivatives representing a range of in vitro activities, from highly active to inactive, for the treatment of pneumocystosis in an immunosuppressed mouse model. Six of these in vitro-active compounds, 01, 02, 04, 06, 100, and 101, exhibited marked efficacies against infection at a dose of 10 mg/kg of body weight, and four compounds, 01, 04, 100, and 101, showed significant increases in survival versus that of untreated infected control mice. Compound 100 was highly efficacious against the infection at 20 mg/kg and 40 mg/kg, with >1,000-fold reductions in burden, and resulted in improved survival curves versus those for pentamidine-treated mice (at the same doses). All six bisbenzamidine compounds that exhibited high in vitro activity significantly decreased the infection in vivo; two compounds, 12 and 102, with marked to moderate in vitro activities had slight or no activity in vivo, while compound 31 was inactive in vitro and was also inactive in vivo. Thus, the selection of highly active compounds from in vitro cytotoxicity assays was predictive of activity in the mouse model of
Pneumocystis
pneumonia. We conclude that a number of these bisbenzamidine compounds, especially compound 100, may show promise as new anti-
Pneumocystis
drugs.
The Cfr rRNA Methyltransferase Confers Resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A Antibiotics
Authors: Long Katherine S. , Poehlsgaard Jacob , Kehrenberg Corinna , Schwarz Stefan , Vester Birte
Published: June 2006

A novel multidrug resistance phenotype mediated by the Cfr rRNA methyltransferase is observed inStaphylococcus aureusandEscherichia coli. Thecfrgene has previously been identified as a phenicol and lincosamide resistance gene on plasmids isolated fromStaphylococcusspp. of animal origin and recently shown to encode a methyltransferase that modifies 23S rRNA at A2503. Antimicrobial susceptibility testing shows thatS. aureusandE. colistrains expressing thecfrgene exhibit elevated MICs to a number of chemically unrelated drugs. The phenotype is named PhLOPSAfor resistance to the following drug classes:Phenicols,Lincosamides,Oxazolidinones,Pleuromutilins, andStreptograminAantibiotics. Each of these five drug classes contains important antimicrobial agents that are currently used in human and/or veterinary medicine. We find that binding of the PhLOPSAdrugs, which bind to overlapping sites at the peptidyl transferase center that abut nucleotide A2503, is perturbed upon Cfr-mediated methylation. Decreased drug binding to Cfr-methylated ribosomes has been confirmed by footprinting analysis. No other rRNA methyltransferase is known to confer resistance to five chemically distinct classes of antimicrobials. In addition, the findings described in this study represent the first report of a gene conferring transferable resistance to pleuromutilins and oxazolidinones.
Clonal Dissemination of a CTX-M-15 β-Lactamase-Producing
Escherichia coli
Strain in the Paris Area, Tunis, and Bangui
Authors: Lavollay M. , Mamlouk K. , Frank T. , Akpabie A. , Burghoffer B. , Ben Redjeb S. , Bercion R. , Gautier V. , Arlet G.
Published: June 2006

One hundred twenty CTX-M-15-producing
Escherichia coli
strains isolated in 10 different hospitals from Paris (France), in the Hospital Charles Nicolle in Tunis (Tunisia), and in the Pasteur Institute in Bangui, Central African Republic (CAR), between 2000 and 2004 were studied. Eighty isolates, recovered from the three countries, were clonally related by repetitive extragenic palindromic PCR and pulsed-field gel electrophoresis. Various resistance profiles were identified among these clonal strains. After conjugation or electroporation of plasmids from
E. coli
strains representative of each profile and each geographic region, we observed seven resistance profiles in the recipient strains. Incompatibility typing showed that all the plasmids transferred from the clonal strains studied, except one, belonged to the incompatibility group FII. They all shared a multidrug resistance region (MDR) resembling the MDR region located in pC15-1a, a plasmid associated with an outbreak of a CTX-M-15-producing
E. coli
strain in Canada. They also shared the common backbone of an apparent mosaic plasmid, including several features present in pC15-1a and in pRSB107, a plasmid isolated from a sewage treatment plant. This study suggests that although the plasmid-borne
bla
CTX-M-15
gene could be transferred horizontally, its dissemination between France, Tunisia, and CAR was due primarily to its residence in an
E. coli
clone with a strong propensity for dissemination.
A Phe389Leu Substitution in ErgA Confers Terbinafine Resistance in
Aspergillus fumigatus
Authors: Rocha E. M. F. , Gardiner R. E. , Park S. , Martinez-Rossi N. M. , Perlin D. S.
Published: June 2006

Replacement of phenylalanine with leucine at position 391 in squalene epoxidase was identified as being responsible for terbinafine resistance in mutants of
Aspergillus nidulans
. The equivalent mutation was engineered into the
ergA
gene of
Aspergillus fumigatus
, resulting in an F389L substitution that also conferred resistance to this pathogenic mold.
Effect of Cell Culture Conditions on the Anticytomegalovirus Activity of Maribavir
Authors: Chou Sunwen , Van Wechel Laura C. , Marousek Gail I.
Published: June 2006

The cytomegalovirus UL97 kinase inhibitor maribavir suppressed viral growth more effectively in lung fibroblasts than in skin fibroblasts, and some cellular kinase inhibitors enhanced its antiviral activity. These effects influence the phenotypic assay of drug susceptibility and suggest the possibility of therapeutically useful combinations of maribavir and cellular kinase inhibitors.
Enteroviral Meningitis: Natural History and Outcome of Pleconaril Therapy
Authors: Desmond R. A. , Accortt N. A. , Talley L. , Villano S. A. , Soong S.-J. , Whitley R. J.
Published: June 2006

Enteroviral meningitis causes appreciable morbidity in adults, including hospitalization, decreased activity, and headache. Limited data define the natural history of disease. No antiviral therapeutic agent has demonstrated improved outcome in controlled clinical trials. Pleconaril, an inhibitor of enterovirus replication, was tested in two placebo-controlled clinical trials. Of 607 randomized patients in a multicenter, double-blind placebo-controlled study of pleconaril (200 mg three times daily versus an identical-appearing placebo), 240 patients were confirmed to have enterovirus infection. The time to headache resolution was evaluated by using Kaplan-Meier survival methodology. A Cox regression model evaluated multivariate factors associated with disease resolution. Resolution of headache in patients with concomitant moderate to severe nausea at baseline occurred at a median of 9.5 days in the absence of therapy and was reduced to 7.0 days for pleconaril recipients (
P
= 0.009). For a headache score of >5 alone, treated patients resolved headache significantly more rapidly (
P
= 0.005). Males resolved headache 50% faster than females. Regardless of randomization group, patients with a baseline headache score of 5 or greater resolved headache 50% more slowly than patients with a baseline headache score of 4. No differences in either clinical or laboratory adverse events were noted. Over 50% of untreated patients had a persistent headache that was greater than 1 week in duration. Pleconaril shortened the course of illness compared to placebo recipients, especially in the early disease course. However, the benefit was achieved only modestly in a subgroup analysis of patients with more severe disease after adjusting for confounding variables.
Activities of Ceftobiprole and Other β-Lactams against
Streptococcus pneumoniae
Clinical Isolates from the United States with Defined Substitutions in Penicillin-Binding Proteins PBP 1a, PBP 2b, and PBP 2x
Authors: Davies Todd A. , Shang Wenchi , Bush Karen
Published: June 2006

The activities of ceftobiprole and other β-lactams were examined with 30
Streptococcus pneumoniae
isolates containing multiple
pbp1a
,
pbp2b
, and
pbp2x
mutations. The highest ceftobiprole MIC was 1 μg/ml, while the comparator MICs were 16 to 64 μg/ml. Fifty percent inhibitory concentrations for penicillin-binding protein 2x were 0.5 μg/ml (ceftobiprole) and 4 μg/ml (ceftriaxone) in a penicillin- and ceftriaxone-resistant isolate.
Interactions between Glycopeptides and β-Lactams against Isogenic Pairs of Teicoplanin-Susceptible and -Resistant Strains of
Staphylococcus haemolyticus
Authors: Vignaroli Carla , Biavasco Francesca , Varaldo Pietro E.
Published: June 2006

Four isogenic derivatives with stably increased glycopeptide MICs (all become resistant to teicoplanin) were obtained from four glycopeptide-susceptible clinical isolates of
Staphylococcus haemolyticus
. All strains were extensively analyzed and compared for a number of distinctive features. In particular, the results provided insights into the puzzling issue of antistaphylococcal interactions between glycopeptides and β-lactams, especially the paradox of double zones around β-lactam disks and the relationships between autolysis rate and type of interaction.
Interaction between Posaconazole and Caspofungin in Concomitant Treatment of Mice with Systemic
Aspergillus
Infection
Authors: Cacciapuoti Anthony , Halpern Judith , Mendrick Cara , Norris Christine , Patel Reena , Loebenberg David
Published: June 2006

The interaction of posaconazole and caspofungin was evaluated in concomitant treatment of
Aspergillus fumigatus
(two strains) or
A. flavus
(one strain) systemic infections in immunocompetent mice. Survival curves for mice treated with the combinations were compared statistically with those for mice treated with the component monotherapies. No antagonism was observed.
Impact of Antimicrobial Dosing Regimen on Evolution of Drug Resistance In Vivo: Fluconazole andCandida albicans
Authors: Andes D. , Forrest A. , Lepak A. , Nett J. , Marchillo K. , Lincoln L.
Published: June 2006

Numerous factors have been theorized to affect the development of antimicrobial resistance, including those specific to the host, the organism, the environment, the drug, and the drug prescriber. One variable under the control of the prescriber is the drug dosing regimen. Dosing regimens can vary in dose level, dosing interval, and treatment duration. The current studies examined the relationships between antimicrobial dosing regimens and resistance development by use of an in vivo model. A murine model of systemicCandida albicansinfection was used to examine resistance emergence during exposure to the triazole antifungal fluconazole. Data from this experimental model demonstrated that the more frequently administered dosing prevented selection of the isogenic resistant cell populations. Conversely, dosing regimens producing prolonged sub-MIC effects appeared to contribute to the outgrowth of isogenic resistant strains. The association between dosing and resistance emergence observed in the current investigation is disparate from that described for antimicrobial compounds with cidal killing characteristics. The inhibitory or static antimicrobial activity of the triazole compounds may explain these differences.
Crystal Structure of the
Mycobacterium fortuitum
Class A β-Lactamase: Structural Basis for Broad Substrate Specificity
Authors: Sauvage Eric , Fonzé Eveline , Quinting Birgit , Galleni Moreno , Frère Jean-Marie , Charlier Paulette
Published: June 2006

β-Lactamases are the main cause of bacterial resistance to penicillins and cephalosporins. Class A β-lactamases, the largest group of β-lactamases, have been found in many bacterial strains, including mycobacteria, for which no β-lactamase structure has been previously reported. The crystal structure of the class A β-lactamase from
Mycobacterium fortuitum
(MFO) has been solved at 2.13-Å resolution. The enzyme is a chromosomally encoded broad-spectrum β-lactamase with low specific activity on cefotaxime. Specific features of the active site of the class A β-lactamase from
M. fortuitum
are consistent with its specificity profile. Arg278 and Ser237 favor cephalosporinase activity and could explain its broad substrate activity. The MFO active site presents similarities with the CTX-M type extended-spectrum β-lactamases but lacks a specific feature of these enzymes, the VNYN motif (residues 103 to 106), which confers on CTX-M-type extended-spectrum β-lactamases a more efficient cefotaximase activity.
In Vivo Fluconazole Pharmacodynamics and Resistance Development in a Previously SusceptibleCandida albicansPopulation Examined by Microbiologic and Transcriptional Profiling
Authors: Andes D. , Lepak A. , Nett J. , Lincoln L. , Marchillo K.
Published: June 2006

Antimicrobial drug resistance can limit the ability to effectively treat patients. Numerous factors have been proposed to impact the development of antimicrobial resistance, including those specific to the drug and the dosing regimen. The field of investigation that examines the relationship between dosing regimen and outcome is termed antimicrobial pharmacokinetics and pharmacodynamics. Our prior in vivo investigations examined the relationship between fluconazole pharmacodynamics and the modulation of isogenic resistant and susceptibleCandida albicanspopulations in a mixed-inoculum design (1). The goal of the current studies was to examine the impact of fluconazole pharmacodynamics on resistance emergence from a susceptible parent population over time using a murine systemic-candidiasis model. Both microbiologic and transcriptional endpoints were examined during the evolution of cell populations. As in our previous investigation, the more frequently administered dosing regimen prevented the emergence of a resistant cell phenotype. Conversely, dosing regimens that produced prolonged sub-MIC concentrations were associated with resistance development. The studies also demonstrated a striking relationship between fluconazole pharmacodynamic exposures and the mRNA abundance of drug resistance-associated efflux pumps. Global transcriptional profiling of cell populations during the progressive emergence of a resistance phenotype provides insight into the mechanisms underlying this complex physiologic process.
Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil
Authors: Zhou Xiao-Jian , Fielman Barbara A. , Lloyd Deborah M. , Chao George C. , Brown Nathaniel A.
Published: June 2006

Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects. Study drugs were administered orally. The pharmacokinetics of telbivudine were characterized by rapid absorption with biphasic disposition. The maximum concentrations in plasma (Cmax) were reached at median times ranging from 2.5 to 3.0 h after dosing. Mean single-doseCmaxand area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) were 1.1 and 2.9 μg/ml and 7.4 and 21.8 μg · h/ml for the 200- and 600-mg telbivudine doses, respectively. Steady state was reached after daily dosing for 5 to 7 days. The mean steady-stateCmaxand area under the plasma concentration-time curve over the dosing interval (AUCτ) were 1.2 and 3.4 μg/ml and 8.9 and 27.5 μg · h/ml for the 200- and 600-mg telbivudine repeat doses, respectively. The steady-state AUCτ of telbivudine was 23 to 57% higher than the single-dose values. Concomitant lamivudine or adefovir dipivoxil did not appear to significantly alter the steady-state plasma pharmacokinetics of telbivudine; the geometric mean ratios and associated 90% confidence interval (CI) for the AUCτ of telbivudine alone versus in combination were 106.3% (92.0 to 122.8%) and 98.6% (86.4 to 112.5%) when coadministered with lamivudine and adefovir dipivoxil, respectively. Similarly, the steady-state plasma pharmacokinetics of lamivudine or adefovir were not markedly affected by the coadministration of telbivudine; the geometric mean ratios and associated 90% CI, alone versus in combination with telbivudine, were 99.0% (87.1 to 112.4%) and 92.2% (84.0 to 101.1%), respectively, for the lamivudine and adefovir AUCτ values. Moreover, the combination regimens studied were well tolerated in all subjects. The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection.
Molecular Evolution of β-Lactam-Resistant
Haemophilus influenzae
: 9-Year Surveillance of Penicillin-Binding Protein 3 Mutations in Isolates from Japan
Authors: Sanbongi Yumiko , Suzuki Takahisa , Osaki Yumi , Senju Nami , Ida Takashi , Ubukata Kimiko
Published: June 2006

A total of 621 clinical isolates of
Haemophilus influenzae
collected in Japan between 1995 and 2003 were studied for their susceptibilities to several antimicrobial agents, β-lactamase production, and amino acid substitutions in penicillin-binding protein 3 (PBP 3). Over the four study periods (first period, 1995 to 1996; second period, 1997 to 1998; third period, 2000 to 2001; fourth period, 2002 to 2003), the susceptibilities to β-lactam agents decreased and the incidence of isolates with substitutions at positions 377, 385, 389, 517, and/or 526 in PBP 3 increased from 28.8% to 52.0%. Five hundred seventy-one β-lactamase-nonproducing isolates were grouped into 18 classes, based on the pattern of the five mutations in PBP 3. The Asp526Lys substitution led to 6.0-, 4.3-, 2.4-, and 5.4-fold increases in amoxicillin-clavulanic acid, cefdinir, cefditoren, and faropenem resistance, respectively. PBP 3 with multiple substitutions (Met377Ile, Ser385Thr, and/or Leu389Phe) together with Asp526Lys resulted in increased resistance compared to that for PBP 3 with the Asp526Lys substitution alone. These results indicate that mutations at these five positions increased resistance to most β-lactams. Although a significant change in the prevalence of β-lactamase-producing strains was not observed, the proportions of those possessing both PBP 3 alterations and β-lactamase production have slightly increased (from 1.4% to 5.0%). The ROB-1 β-lactamase was rare, but this is the first report of this β-lactamase in Japan.
Aziridine-2,3-Dicarboxylates, Peptidomimetic Cysteine Protease Inhibitors with Antileishmanial Activity
Authors: Ponte-Sucre Alicia , Vicik Radim , Schultheis Martina , Schirmeister Tanja , Moll Heidrun
Published: June 2006

Chemotherapy of leishmaniasis is mainly based on antimonials. However, they are extremely toxic and cause serious side effects, and there is a worldwide increasing frequency of chemoresistance to antimonials. These issues emphasize the urgent need for affordable alternative drugs against leishmaniasis.Leishmaniacysteine proteases are essential for parasite growth, differentiation, pathogenicity, and virulence and are thus attractive targets for combating leishmaniasis. Herein we demonstrate that the cysteine protease inhibitors aziridine-2,3-dicarboxylates 13b and 13e impaired promastigote growth at mid-micromolar concentrations and decreased the infection rate of peritoneal macrophages at concentrations 8- to 13-fold lower than those needed to inhibit parasite replication. Simultaneous treatment of infected cells with compound 13b and gamma interferon resulted in an even further reduction of the concentration needed for a significant decrease in macrophage infection rate. Notably, treatment with the compounds alone modulated the cytokine secretion of infected macrophages, with increased levels of interleukin-12 and tumor necrosis factor alpha. Furthermore, the decreased infection rate in the presence of compound 13b correlated with increased nitric oxide production by macrophages. Importantly, at the concentrations used herein, compounds 13b and 13e were not toxic against fibroblasts, macrophages, or dendritic cells. Together, these results suggest that the aziridine-2,3-dicarboxylates 13b and 13e are potential antileishmanial lead compounds with low toxicity against host cells and selective antiparasitic effects.
In Vitro and In Vivo Assessment of Linezolid Combined with Ertapenem: a Highly Synergistic Combination against Methicillin-Resistant
Staphylococcus aureus
Authors: Jacqueline Cedric , Caillon Jocelyne , Grossi Olivier , Le Mabecque Virginie , Miegeville Anne-Françoise , Bugnon Denis , Batard Eric , Potel Gilles
Published: June 2006

Linezolid in combination with ertapenem showed in vitro synergy against methicillin-resistant
Staphylococcus aureus
strains. We confirmed this interaction in vivo by using a rabbit endocarditis experimental model and simulation of the human pharmacokinetics in animals for both antibiotics. Linezolid plus ertapenem exhibited highly synergistic activity in vivo after 4 days of treatment.
Results Obtained with Various Antifungal Susceptibility Testing Methods Do Not Predict Early Clinical Outcome in Patients with Cryptococcosis
Authors: Dannaoui E. , Abdul M. , Arpin M. , Michel-Nguyen A. , Piens M. A. , Favel A. , Lortholary O. , Dromer F. ,   the French Cryptococcosis Study Group
Published: June 2006

The in vitro susceptibilities of
Cryptococcus neoformans
isolates from consecutive human immunodeficiency virus-positive and -negative patients to the antifungal agents fluconazole, amphotericin B, and flucytosine were determined by different techniques, including the CLSI method, Etest, and broth microdilution in yeast nitrogen base (YNB) medium, during a multicenter prospective study in France. The relationship between the in vitro data and the clinical outcome 2 weeks after the initiation of antifungal therapy was assessed. In addition, the correlation between the strain serotype and the in vitro activities of the antifungals was determined, and the susceptibility results obtained with the different techniques were also compared. Thirty-seven patients received a combination of amphotericin B with flucytosine as first-line therapy, 22 were treated with amphotericin B alone, and 15 received fluconazole alone. Whatever the antifungal tested, there was no trend toward higher MICs for strains isolated from patients who failed to respond to a given therapy compared to those from patients who did not with either the CLSI method, Etest, or broth microdilution in YNB medium. The MICs obtained by the CLSI or Etest method were significantly lower for serotype D strains than for serotype A strains for both fluconazole and amphotericin B, while flucytosine MICs were not different according to serotype. These findings suggest that the in vitro antifungal susceptibility of
C. neoformans
, as determined with the techniques used, is not able to predict the early clinical outcome in patients with cryptococcosis.
Interaction of Antimicrobial Peptide Temporin L with Lipopolysaccharide In Vitro and in Experimental Rat Models of Septic Shock Caused by Gram-Negative Bacteria
Authors: Giacometti Andrea , Cirioni Oscar , Ghiselli Roberto , Mocchegiani Federico , Orlando Fiorenza , Silvestri Carmela , Bozzi Argante , Di Giulio Antonio , Luzi Carla , Mangoni Maria Luisa , Barra Donatella , Saba Vittorio , Scalise Giorgio , Rinaldi Andrea C.
Published: June 2006

Sepsis remains a major cause of morbidity and mortality in hospitalized patients, despite intense efforts to improve survival. The primary lead for septic shock results from activation of host effector cells by endotoxin, the lipopolysaccharide (LPS) associated with cell membranes of gram-negative bacteria. For these reasons, the quest for compounds with antiendotoxin properties is actively pursued. We investigated the efficacy of the amphibian skin antimicrobial peptide temporin L in bindingEscherichia coliLPS in vitro and counteracting its effects in vivo. Temporin L strongly bound to purifiedE. coliLPS and lipid A in vitro, as proven by fluorescent displacement assay, and readily penetrated intoE. coliLPS monolayers. Furthermore, the killing activity of temporin L againstE. coliwas progressively inhibited by increasing concentrations of LPS added to the medium, further confirming the peptide's affinity for endotoxin. Antimicrobial assays showed that temporin L interacted synergistically with the clinically used β-lactam antibiotics piperacillin and imipenem. Therefore, we characterized the activity of temporin L when combined with imipenem and piperacillin in the prevention of lethality in two rat models of septic shock, measuring bacterial growth in blood and intra-abdominal fluid, endotoxin and tumor necrosis factor alpha (TNF-α) concentrations in plasma, and lethality. With respect to controls and single-drug treatments, the simultaneous administration of temporin L and β-lactams produced the highest antimicrobial activities and the strongest reduction in plasma endotoxin and TNF-α levels, resulting in the highest survival rates.
Mechanism of Drug Resistance in Clonally Related Clinical Isolates of
Vibrio fluvialis
Isolated in Kolkata, India
Authors: Srinivasan Vijaya Bharathi , Virk Rupinder Kaur , Kaundal Amita , Chakraborty Rupa , Datta Basabjit , Ramamurthy T. , Mukhopadhyay Asish K. , Ghosh Amit
Published: June 2006

The molecular mechanisms of drug resistance in 19 strains of
Vibrio fluvialis
isolated from 1998 to 2002 in Kolkata, India, were investigated. Class 1 integrons were detected in eight strains, and four strains were found to carry SXT integrases. In the presence of carbonyl cyanide
m
-chlorophenylhydrazone or reserpine, all nalidixic acid- and ciprofloxacin-resistant strains became sensitive, suggesting that drug efflux plays a major role in quinolone resistance in
V. fluviali
s. It was further seen that strains which had MICs of >25 μg/ml for nalidixic acid had a sense mutation (Ser to Ile) at position 83 of the quinolone resistance-determining region of
gyrA
. All except one of the integron- and SXT integrase-bearing strains belonged to the same ribotype.
DYNAMICAL SYMMETRY IN GRAVITATIONAL COLLAPSE WITH GENERAL INITIAL AREA RADIUS
Authors: CHAKRABORTY SUBENOY , CHAKRABORTY SANJUKTA
Published: June 2006

In this work, gravitational collapse has been studied for quasi-spherical spacetime with dust or anisotropic pressure as the matter content. A linear transformation on the initial data set and of the area radius shows the invariance of the physical parameters as well as the final fate of collapse, considering an arbitrary function of r as the initial area radius.
MASSLESS THREE-DIMENSIONAL QUANTUM ELECTRODYNAMICS AND THIRRING MODEL CONSTRAINED BY LARGE FLAVOR NUMBER
Authors: FAZIO A. R.
Published: June 2006

We explicitly prove that in three-dimensional massless quantum electrodynamics at finite temperature, zero density and large number of flavors, the number of infrared degrees of freedom is never larger than the corresponding number of ultraviolet. Such a result, strongly dependent on the asymptotic freedom of the theory, is reversed in three-dimensional Thirring model due to the positive derivative of its running coupling constant.
HIGGS PHENOMENOLOGY WITH CPsuperH
Authors: ELLIS JOHN , LEE JAE SIK , PILAFTSIS APOSTOLOS
Published: June 2006

The MSSM contains CP-violating phases that may have important observable effects in Higgs physics. We review recent highlights in Higgs phenomenology obtained with the code CPsuperH, a useful tool for studies of the production, mixing and decay of a coupled system of the neutral Higgs bosons at future high energy colliders such as the LHC, ILC (γLC), and a muon collider (MC). CPsuperH implements the constraints from upper limits on electric dipole moments, and may be extended to include other related low-energy observables, such as b→sγ and B→Kl l, and to compute the relic abundance of the lightest neutralino.
Leveraging Technological Capabilities across Polarized Cultures: Shanghai Delco Electronics Limited
Authors: Ojode Lucy A.
Published: June 2006

Rallying its units for an impending spin-off from General Motors, the Delphi Automotive Systems division cleared the Delphi Delco Electronics (Delphi-D) unit to begin planning for entry into China in 1994. Delphi saw China as ideal for leveraging its technological and innovation capabilities as well as the enormous General Motor heritage and reputation from years of experience delivering quality products to the automotive industry. Delphi-D found a perfect partner in Shanghai Changjiang YiBiao Factory (SCY) (name disguised to protect the firms) that held nearly 50% of the Chinese automobile instrument cluster market. SCY was keen on acquiring new technology to meet increasingly sophisticated customer demands in order to retain market lead as well as to tap into the international market.

After rounds of negotiation the two firms formed a fifty-fifty joint venture, Shanghai Delco Electronics Ltd. (SDE) in August 1996. However, SDE started experiencing problems almost immediately. The Delphi-D team at SDE assumed their SCY counterparts would willingly integrate proposed technology and the requisite processes at the joint venture. However, the SCY team resisted prescriptions from the Delphi-D team that they sometimes perceived as "haughty". Broiled in culturally-loaded misunderstanding in a market that was becoming complex by the day as the government legislated new regulations and other manufacturers jostled for a piece of the market, SDE's management sought focus by developing a five-year plan that captured the partners' goals in 1998. However, as the end of 2002 approached, SDE's five-year plan remained largely unrealized. This case shows how implementation challenges can affect the realization of joint venture objectives and illustrates specific challenges that can mar even a well-formulated technology intensive international joint venture strategy.
Packages and Mitsubishi — International Joint Venture Negotiations
Authors: Arif Humaira , Nazir Butt Arif
Published: June 2006

This case covers the negotiations between Packages Limited, Pakistan (Packages) and Mitsubishi Corporation, Japan (Mitsubishi) for the formation of a joint venture to produce Biaxially Oriented Polypropylene (BOPP) film in Pakistan. Packages was established in Pakistan in 1957 as a joint venture between the Wazir Ali Group and AB Auckerland and Rausing of Sweden. Packages manufactured paper and board and converted them to packaging products. Mitsubishi was one of the biggest conglomerates in Japan, operating internationally. In 1992, Syed Babar Ali, founder and advisor to Packages proposed establishing a joint venture with Mitsubishi, during his visit to Japan. Upon returning to Pakistan, he asked Packages' senior management to negotiate a joint venture agreement with Mitsubishi. Both Packages and Mitsubishi agreed in principle to establish a joint venture to manufacture BOPP film in Pakistan.

In this case, the negotiation process was divided into three phases. The case describes the issue discussed and tactics employed by the two sides during the three phases. The major issues discussed included the price and capacity of the plant, the reimbursement of Mitsubishi's investment if the company suffered repeated losses, raw material supply from Mitsubishi, equity participation, and the control of the management and the board of the new company. In April, 1993, Mr. Javed Aslam, the Deputy General Manager of Packages, received a quotation of US $6.4 million for a 6000-ton plant from Mitsubishi Heavy Industries (MHI). He had to decide if it was feasible for Packages to go ahead with the joint venture with Mitsubishi and what counter offer to make to Mitsubishi Heavy Industries.
Sau San Tong: A Paragon of the Slimming and Beauty Business
Authors: Tai Susan
Published: June 2006

Sau San Tong Holdings was established in July 2000 and initially sold Chinese herbal slimming medicines. In 2001, it moved into the full-body slimming business. Within three years, the company had transformed itself into a Growth Enterprise Market listed company, operating four slimming centres in Hong Kong and two in Shanghai. The major shareholder, Shirley Cheung Yuk Shan (the former TV artist) controlled over 50% of the company. Shirley Cheung, who had strong marketing skills and a special talent in selecting celebrities as successful and persuasive spokespersons, had developed Sau San Tong into a paragon of the slimming and beauty business. This case explores marketing strategy and communications for a service.
BOND MARKET MODEL
Authors: BAVIERA ROBERTO
Published: June 2006

We describe the Bond Market Model, a multi-factor interest rate term structure model, where it is possible to price with Black-like formulas the three classes of over-the-counter plain vanilla options. We derive the prices of caps/floors, bond options and swaptions. A comparison with Libor Market Model and Swap Market Model is discussed in detail, underlining advantages and limits of the different approaches.
MONTE CARLO EVALUATION OF AMERICAN OPTIONS USING CONSUMPTION PROCESSES
Authors: BELOMESTNY DENIS , MILSTEIN GRIGORI N.
Published: June 2006

We develop a new approach for pricing both continuous-time and discrete-time American options which is based on the fact that any American option is equivalent to a European one with a consumption process involved. This approach admits the construction of an upper bound (a lower bound) on the true price using some lower bound (an upper bound) by Monte Carlo simulation. A number of effective estimators of upper and lower bounds with the reduced variance are proposed. The method is supported by numerical experiments which look promising.
PRICING AND HEDGING AMERICAN BARRIER OPTIONS BY A MODIFIED BINOMIAL METHOD
Authors: GAUDENZI MARCELLINO , LEPELLERE MARIA ANTONIETTA
Published: June 2006

The aim of this work is to present a modification of the standard binomial method which allows to price American barrier options improving the efficiency of the trinomial methods. Our approach is based on a suitable interpolation of binomial values and allows to price and hedge such options also in the critical case of near barriers. All the different types of single barrier options are considered, in the case of knock-in barriers a new implementation of the binomial method is provided.
PRICING PARTICIPATING POLICIES WITH RATE GUARANTEES
Authors: CHU CHI CHIU , KWOK YUE KUEN
Published: June 2006

We construct the contingent claims models that price participating policies with rate guarantees and default risk. These policies are characterized by the sharing of profits from an investment portfolio between the insurer and the policyholders. A certain reserve distribution mechanism is employed to credit interest at or above certain specified guaranteed rate periodically to the policyholders. Besides the reversionary reserve distribution, terminal bonus is also paid to the policyholders if the terminal surplus is positive. However, the insurer may default at maturity and the policyholders can only receive the residual assets. By neglecting market frictions, mortality risk and surrender option, and under certain assumptions on the interest rate crediting mechanism, we are able to find analytic approximation solution to the pricing model using perturbation techniques. We also develop effective finite difference algorithms for the numerical solution of the contingent claims models. Pricing behaviors of these participating policies with respect to various parameters in the pricing models are examined.
CRASH HEDGING STRATEGIES AND WORST-CASE SCENARIO PORTFOLIO OPTIMIZATION
Authors: MENKENS OLAF
Published: June 2006

Crash hedging strategies are derived as solutions of non-linear differential equations which itself are consequences of an equilibrium strategy which make the investor indifferent to uncertain (down) jumps. This is done in the situation where the investor has a logarithmic utility and where the market coefficients after a possible crash may change. It is scrutinized when and in which sense the crash hedging strategy is optimal. The situation of an investor with incomplete information is considered as well. Finally, introducing the crash horizon, an implied volatility is derived.
PROJECTIVE AND CONFORMAL SCHWARZIAN DERIVATIVES AND COHOMOLOGY OF LIE ALGEBRAS VECTOR FIELDS RELATED TO DIFFERENTIAL OPERATORS
Authors: BOUARROUDJ SOFIANE
Published: June 2006

Let M be either a projective manifold (M, Π) or a pseudo-Riemannian manifold (M, g). We extend, intrinsically, the projective/conformal Schwarzian derivatives we have introduced recently, to the space of differential operators acting on symmetric contravariant tensor fields of any degree on M. As operators, we show that the projective/conformal Schwarzian derivatives depend only on the projective connection Π and the conformal class of the metric [g], respectively. Furthermore, we compute the first cohomology group of Vect(M) with coefficients in the space of symmetric contravariant tensor fields valued in the space of δ-densities, and we compute the corresponding sl(n + 1, ℝ)-relative cohomology group.
ON THE SYMMETRY BREAKING PHENOMENON
Authors: BIRTEA PETRE , PUTA MIRCEA , RATIU TUDOR S. , TUDORAN RĂZVAN MICU
Published: June 2006

We investigate the problem of symmetry breaking in the framework of dynamical systems with symmetry on a smooth manifold. Two cases will be analyzed: general and Hamiltonian dynamical systems. We give sufficient conditions for symmetry breaking in both cases.
HERMITIAN VECTOR FIELDS AND SPECIAL PHASE FUNCTIONS
Authors: JANYŠKA JOSEF , MODUGNO MARCO
Published: June 2006

We start by analyzing the Lie algebra of Hermitian vector fields of a Hermitian line bundle. Then, we specify the base space of the above bundle by considering a Galilei, or an Einstein spacetime. Namely, in the first case, we consider, a fibred manifold over absolute time equipped with a spacelike Riemannian metric, a spacetime connection (preserving the time fibring and the spacelike metric) and an electromagnetic field. In the second case, we consider a spacetime equipped with a Lorentzian metric and an electromagnetic field. In both cases, we exhibit a natural Lie algebra of special phase functions and show that the Lie algebra of Hermitian vector fields turns out to be naturally isomorphic to the Lie algebra of special phase functions. Eventually, we compare the Galilei and Einstein cases.
Investigations on the Involvement of the Lectin Pathway of Complement Activation in Anaphylaxis
Authors: Windbichler Michaela , Echtenacher Bernd , Takahashi Kazue , Ezekowitz R. Alan B. , Schwaeble Wilhelm J. , Jenseniuis Jens C. , Männel Daniela N.
Published: June 2006

Background: Systemic anaphylaxis is the most severe form of immediate hypersensitivity reaction. The activation of the complement system occurs during anaphylactic shock. The purpose of this study was to determine in a mouse model whether the lectin pathway of complement activation is involved in anaphylaxis. Methods: To see whether the lectin pathway is involved in anaphylactic shock, serum mannan-binding lectin (MBL) levels were measured after passive anaphylaxis. Also MBL expression and binding to potential ligands were investigated. To determine whether complement or mast cell activation is essential for hypothermia in anaphylactic shock, mouse strains deficient in MBL-A and MBL-C, C1q, factors B and C2, C5, C5aR, or mast cells were tested. Results: After antigenic challenge a marked drop in body temperature as well as a rapid decrease in serum MBL levels were observed. The decrease of serum MBL levels in shock could not be attributed to MBL binding to immune complexes or tissues, but an interaction of MBL with mast cell-derived proteoglycans was seen. In contrast to mast cell-deficient mice, none of the complement-deficient mouse strains were protected from shock-associated hypothermia. Conclusions: These results indicate that neither MBL nor activation of the complement cascade is crucial for the induction of anaphylaxis. In contrast mast cell activation is associated with the development of hypothermia and possibly the observed decrease in serum MBL levels.
Delayed Allergic Reaction to Suxamethonium Driven by Oligoclonal Th1-Skewed CD4+CCR4+IFN-γ+ Memory T Cells
Authors: Scala Enrico , Guerra Emma C. , Giani Mauro , Pirrotta Lia , Locanto Maria , Mondino Chiara , Mari Adriano
Published: June 2006

Background: Muscle relaxants represent the drugs most frequently involved in intraoperative anaphylaxis during surgical procedures. Our aim was to report the case of a delayed reaction to suxamethonium and analyze specific T cell lines with regard to their specificity, phenotype and cytokine profile. Methods: We generated a drug-specific T cell line from a biopsy at the site of positive intradermal reactions and analyzed the immunophenotype, T cell receptor Vβ domain expression and cytokine profile. Results: T cells isolated from positive intradermal test reactions to suxamethonium showed a strict dose-dependent proliferation in response to drug-pulsed autologous antigen-presenting cells. The drug-specific CD4+ T cells were oligoclonal memory CD3+CD4+ T cells and expressed the skin homing receptors cutaneous lymphocyte antigen (CLA) and CCR4. Furthermore CD4+ suxamethonium-reactive T cell lines were IFN-γ-positive and synthesized high levels of IFN-γ and TNF-α. Conclusion: The study describes a delayed hypersensitivity to suxamethonium, driven by an oligoclonal T helper cell 1-skewed CD4+ memory T cell population, expressing the skin homing receptors CLA and CCR4.
One-Year Evaluation of the Preventative Effect of Hydrofluoroalkane-Beclomethasone Dipropionate on Eosinophilic Inflammation of Asthmatic Peripheral Airways
Authors: Ohbayashi Hiroyuki
Published: June 2006

Background: In asthmatic patients with eosinophilic inflammation of the peripheral airways, appropriate drug delivery to the affected area is required. Objective: It was the aim of this study to assess persistent eosinophilic inflammation of the peripheral airways in asthmatic patients, stabilized by the long-term use of dry powder type inhaled steroids, and to evaluate the clinical efficacy of hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) over 1 year. Methods: Seventy-four outpatients with moderate stable asthma were studied for at least 6 months, 37 treated with fluticasone propionate Diskus® (FP-DK) and 37 with budesonide Turbuhaler® (BUD-TH). The eosinophil count, eosinophil cationic protein (ECP), eotaxin and RANTES levels in 10% hypertonic saline-induced sputum were examined before treatment, as well as 4 weeks, 8 weeks, 6 months and 1 year after switching patients to HFA-BDP. Results: Fifteen patients (40.5%) in the FP-DK group and 12 (32.4%) in the BUD-TH group had eosinophils in induced sputum. The sputum ECP in the eosinophil-positive and the eosinophil-negative groups was 1,510.1 ± 2,009.3 versus 426.6 ± 464.1 µg/l (p = 0.037) in the FP-DK group, and 3,850.0 ± 5,486.2 versus 492.0 ± 1,150.7 µg/l (p = 0.011) in the BUD-TH group, respectively. Four weeks after the switch to HFA-BDP, the number of eosinophil-positive patients decreased in both groups. Significant reductions in sputum ECP and eotaxin were observed at 8 weeks, and their concentrations continued decreasing for 1 year. Conclusion: There is a certain proportion of asthmatic patients for whom long-term treatment with dry powder type steroids may not be suitable; however, their peripheral airway inflammation improved after switching them to HFA-BDP, suggesting its excellent delivery.
Effects of a New Hormone Therapy, Drospirenone and 17-β-Estradiol, in Postmenopausal Women With Hypertension
Authors: White William B. , Hanes Vladimir , Chauhan Vijay , Pitt Bertram
Published: June 2006

Drospirenone (DRSP), a progestin with antialdosterone activity, has been developed for hormone therapy in combination with 17-β-estradiol (E2) in postmenopausal women. We evaluated the antihypertensive efficacy and safety of various doses of DRSP and E2 and estradiol alone in postmenopausal women with hypertension using ambulatory and clinic blood pressure (BP) monitoring. This was a randomized, double-blind clinical trial of 3 doses of DRSP combined with estradiol, estradiol alone, and placebo in 750 postmenopausal women with stage 1 to 2 hypertension between 45 to 75 years. Ambulatory and clinic BPs, potassium, aldosterone, and lipid measurements and adverse events were evaluated in postmenopausal women with stages 1 to 2 hypertension during 8 weeks of double-blind therapy. DRSP and E2 induced dose-related reductions in the ambulatory and clinic systolic BP with physiological increases in serum aldosterone. Significant decreases in 24-hour systolic pressure were observed at doses of 2 and 3 mg of DRSP combined with estradiol but not by estradiol alone or 1 mg of DRSP with estradiol. There were no significant changes from baseline in potassium in any treatment group. Small, significant reductions in total and low-density lipoprotein cholesterol occurred on all of the active treatments, and serum triglycerides did not change. Adverse event rates were low and similar across treatment groups. In conclusion, these data show that DRSP combined with E2 significantly reduces BP in postmenopausal women with hypertension and did not induce significant increases in serum potassium. These characteristics may lead to a new benefit for this novel hormone therapy in postmenopausal women with hypertension.
Quality of Life of Spouses of Mentally Ill People
Authors: Angermeyer Matthias C. , Kilian Reinhold , Wilms Hans-Ulrich , Wittmund Bettina
Published: June 2006

Background: Spouses of people with mental disorder experience various forms of objective and subjective burden. This should negatively affect their quality of life. However, until now no single study has addressed this question.

Aims: To investigate the quality of life of spouses of people with schizophrenia, depression or anxiety disorders.

Method: Spouses of patients suffering from schizophrenia (n 1/4 45), depression (n 1/4 49) and anxiety disorders (n 1/4 39) were consecutively recruited from out-patient services in the city of Leipzig. Quality of life was assessed by means of the WHOQOL-BREF, a self-administered questionnaire developed by the World Health Organisation.

Results: Compared with the general population, the quality of life of the spouses of mentally ill people was lower in the domains ‘psychological well-being’ and ‘social relationships’. There was a significant association between the patient's functional level and the spouse's quality of life.

Conclusions: Better treatment, professional support and participation in self-help and advocacy groups may help to improve the quality of life of spouses of mentally ill people.