bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACT

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

ABSTRACTAntimicrobial 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

ABSTRACTTwo 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

ABSTRACT

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

ABSTRACTChemotherapy 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

ABSTRACT

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

ABSTRACT

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

ABSTRACTSepsis 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

ABSTRACT

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.
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.
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.
Cross-Cultural Validation of Expressed Emotion in Caregivers of Chinese Patients with First Episode Psychosis in Singapore: A Qualitative Study
Authors: Healey Frances , Tan Vicky L.M. , Chong S. A. 
Published: June 2006

Background: The concept of Expressed Emotion (EE; Brown et al., 1972), a measure of criticism, over-involvement and hostility in families, has been shown to be a robust predictor of relapse in schizophrenia (Parker & Hadzi-Pavlovic, 1990). Recent criticism of using Western instruments in Asian countries has led to more stringent procedures for validation of scales. Aims: The first aim was to establish that the concept of Expressed Emotion exists in Singapore. The second aim was to examine the Level of Expressed Emotion (LEE; Cole & Kazarian, 1988, Gerlsma & Hale, 1997) scale to ascertain the conceptual and construct operationalisation of this instrument in this culture. Methods: This was a qualitative study. The concept of EE was examined using a Singaporean population; 10 patient–caregiver pairs were recruited and interviewed using a semi-structured interview format. Regarding the LEE, small focus-group interviews were conducted with a cross-section of Singaporeans to gain their views on the concepts in the scale and the relevance of the items in this culture. Results: The interviews were analysed in light of attitudes found to discriminate between high and low EE families (Leff & Vaughn, 1985). A clear distinction between high and low EE groups was found. With regard to the LEE, the data from the focus groups, for the most part, supported the cross-cultural conceptual and operational equivalence of the scale and suggestions for additional items were made. Conclusion: There is support for the existence of EE among families in Singapore, and the LEE was found, for the most part, to be applicable in Singapore, with the addition of several emic items.
Common-Sense Descriptions of Depression as Social Representations
Authors: Räty Hannu , Ikonen Seija , Honkalampi Kirsi 
Published: June 2006

Background: Major depression is such a prevalent illness worldwide that practically everyone has either direct or indirect experience of it. It is important, then, from both practical and theoretical points of view, to examine this particular experience and related conceptions. Aim: Drawing on the theory of social representations, this research set out to examine the ways in which people define depression in terms of the symptoms they attribute to people they know personally and consider to suffer from depression. Method: A group of adult participants (n = 117) were instructed to think of an individual whom they knew personally and considered to suffer from depression, to indicate the age and gender of the person, and to describe his/her symptoms. Results: A great majority of the female participants thought of a female, while the male participants thought of male and female target persons quite evenly. The symptoms attributed to depression with fair unanimity included fatigue and decreased capacity to work, to concentrate, to make decisions and to take part in hobbies. The descriptions of the depressive person were quite unanimously distinguished from the signal symptoms attaching to schizophrenia. The descriptions varied according to the characteristics of the target individuals, and their gender and age in particular, rather than the characteristics of the participants. Conclusion: People have perceptive personal experiences of depression, which are guided by socially shared interpretative frameworks.